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Park J, Shimbo H, Tamura S, Tomoda T, Hikida T, Okado H, Hirai S. Impact of feeding age on cognitive impairment in mice with Disrupted-In-Schizophrenia 1 (Disc1) mutation under a high sucrose diet. Behav Brain Res 2025; 476:115291. [PMID: 39401692 DOI: 10.1016/j.bbr.2024.115291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 10/17/2024]
Abstract
A combination of genetic predisposition and environmental factors contributes to the development of psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder. Previous studies using mouse models suggested that prolonged high sucrose intake during puberty can serve as an environmental risk factor for the onset of psychiatric disorders. However, the impact of both the duration and timing of high sucrose consumption during different developmental stages on pathogenesis remains poorly defined. We therefore investigated the effects of a long-term high sucrose diet on cognitive deficit, a core symptom of psychiatric disorders, using Disrupted-in-Schizophrenia 1 locus-impairment heterozygous mutant (Disc1het) mice as a model for genetic predisposition. First, Disc1het mice and their littermate control (WT) were fed either a high sucrose diet or a control starch diet for nine weeks starting at weaning (postnatal day 24), and tested for cognitive performance in the object location test (OLT) and the novel object recognition test (NORT) (assessing spatial and recognition memory, respectively). Only Disc1het mice on a high sucrose diet displayed deficits in OLT (p < 0.0001), demonstrating impaired hippocampus-dependent spatial memory. This behavioral abnormality was accompanied by a decreased proportion of the high parvalbumin-expressing interneurons (High-PV neurons) in the ventral hippocampus, a cell type that regulates neural activity and a variety of learning and memory processes such as spatial and working memory. We further explored the critical developmental period for high sucrose intake to cause cognitive deficits in adulthood by comparing specific feeding periods during puberty (P24-P65) and post-puberty (P65-P90). Compared to those on a standard chow diet, high sucrose intake caused deficits in spatial memory in both WT and Disc1het mice, with more pronounced effects in Disc1het mice. In particular, Disc1het mice on a sucrose diet during adolescence showed more pronounced cognitive deficit than those fed after adolescence. Our results suggest that adolescence is particularly vulnerable to nutritional environmental risk factors, and that high sucrose consumption may cause hippocampus-dependent memory deficits via decreased High-PV interneuron function when combined with Disc1-related genetic predisposition.
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Affiliation(s)
- Jonghyuk Park
- Metabolic Regulation Group, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Japan
| | - Hiroko Shimbo
- Metabolic Regulation Group, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Japan; Clinical Research Institute, Kanagawa Children's Medical Center, Japan
| | - Shoko Tamura
- Metabolic Regulation Group, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Japan
| | - Toshifumi Tomoda
- Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, University of Toronto, Canada
| | - Takatoshi Hikida
- Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Japan
| | - Haruo Okado
- Metabolic Regulation Group, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Japan
| | - Shinobu Hirai
- Metabolic Regulation Group, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Japan.
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Mao Z, Dong F, Li A, Li F, Zhu J, Du X, Wu G, Deng H, Yu X, Liu J, Xie S, Tang X, Wang G. Effectiveness and safety of aripiprazole oral solution in the acute treatment of schizophrenia in Chinese patients. BMC Psychiatry 2024; 24:959. [PMID: 39734212 DOI: 10.1186/s12888-024-06455-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 12/26/2024] [Indexed: 12/31/2024] Open
Abstract
BACKGROUND This study investigates the effectiveness and safety of aripiprazole oral solution in Chinese patients with schizophrenia. METHODS This was a multicenter, single-arm phase IV study involving 134 patients in China in the acute stage of schizophrenia from May 2021 to July 2022. The patients received aripiprazole oral solution 10 - 30 mg/d for 12 weeks. The effectiveness endpoints included the Positive and Negative Symptom Scale (PANSS) and the Clinical Global Impression (CGI) scale score. The safety endpoints included adverse events, laboratory inspection indicators (including the serum prolactin level [PRL]), and waist circumferences (WC). RESULTS Ultimately, 86 patients (64.18%) completed the trial, and 21 patients (15.67%) dropped out due to poor effectiveness. From baseline to week eight, 43.28% of patients had a PANSS reduction of ≥ 50%, 82.84% of patients improved in the CGI-Improvement (CGI-I scale score of 1 - 3), and the percentage of patients with abnormal PRL and waist circumferences decreased significantly. In total, 45 patients (33.58%) experienced mild adverse drug reactions predominately manifested as extrapyramidal symptoms (EPSs; 9.70%), constipation (8.96%), and palpitations (7.46%). Upon further subgroup analysis, aripiprazole oral solution demonstrated significantly improved effectiveness in first-episode schizophrenia patients and those with symptoms of agitation. CONCLUSIONS Aripiprazole oral solution displayed positive clinical effectiveness and favorable tolerability in Chinese patients in the acute stage of schizophrenia. CLINICAL TRIAL REGISTRATION Clinical trial registration number: ChiCTR2100044653. Name of trial registration: A real-world study of Aripiprazole Oral Solution in the treatment of schizophrenia (Registration date: 25/03/2021). The full trial protocol can be accessed at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ).
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Affiliation(s)
- Zhen Mao
- The National Clinical Research Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China
| | - Fang Dong
- The National Clinical Research Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China
| | - Anning Li
- The National Clinical Research Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China
| | - Feng Li
- The National Clinical Research Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China
| | - Junhong Zhu
- Wuhan Mental Health Center, Wuhan, 430012, China
| | - Xiangdong Du
- The Affiliated Guangji Hospital of Soochow University, Suzhou, 215137, China
| | - Gang Wu
- The Second People's Hospital of Guizhou Province, Guizhou, 550081, China
| | - Huaili Deng
- Shanxi Provincial Mental Health Center, Shanxi, 030045, China
| | - Xueqin Yu
- Chongqing Mental Health Center, Chongqing, 400036, China
| | - Jintong Liu
- Shandong Mental Health Center, Jinan, 250014, China
| | - Shiping Xie
- The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaowei Tang
- Affiliated WuTaiShan Hospital of Medical College of Yangzhou University, Yangzhou, 225003, China
| | - Gang Wang
- The National Clinical Research Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China.
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China.
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Brand BA, de Boer JN, Willemse EJM, Weickert CS, Sommer IE, Weickert TW. Antipsychotic-induced prolactin elevation in premenopausal women with schizophrenia: associations with estrogen, disease severity and cognition. Arch Womens Ment Health 2024; 27:931-941. [PMID: 38995314 PMCID: PMC11579114 DOI: 10.1007/s00737-024-01491-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 06/26/2024] [Indexed: 07/13/2024]
Abstract
PURPOSE Antipsychotic-induced prolactin elevation may impede protective effects of estrogens in women with schizophrenia-spectrum disorders (SSD). Our study sought to confirm whether the use of prolactin-raising antipsychotics is associated with lower estrogen levels, and to investigate how estrogen and prolactin levels relate to symptom severity and cognition in premenopausal women with SSD. METHODS This cross-sectional study included 79 premenopausal women, divided in three groups of women with SSD treated with prolactin-sparing antipsychotics (n = 21) or prolactin-raising antipsychotics (n = 27), and age-matched women without SSD (n = 31). Circulating 17β-estradiol was compared among groups. In patients, we assessed the relationship between prolactin and 17β-estradiol, and the relationships of these hormones to symptom severity and cognition, using correlation analyses and backward regression models. RESULTS In women receiving prolactin-raising antipsychotics, 17β-estradiol levels were lower as compared to both other groups (H(2) = 8.34; p = 0.015), and prolactin was inversely correlated with 17β-estradiol (r=-0.42, p = 0.030). In the prolactin-raising group, 17β-estradiol correlated positively with verbal fluency (r = 0.52, p = 0.009), and 17β-estradiol and prolactin together explained 29% of the variation in processing speed (β17β-estradiol = 0.24, βprolactin = -0.45, F(2,25) = 5.98, p = 0.008). In the prolactin-sparing group, 17β-estradiol correlated negatively with depression/anxiety (r = -0.57, p = 0.014), and together with prolactin explained 26% of the variation in total symptoms (β17β-estradiol = -0.41, βprolactin = 0.32, F(2,18) = 4.44, p = 0.027). CONCLUSIONS In women with SSD, antipsychotic-induced prolactin elevation was related to lower estrogen levels. Further, estrogens negatively correlated with symptom severity and positively with cognition, whereas prolactin levels correlated negatively with cognition. Our findings stress the clinical importance of maintaining healthy levels of prolactin and estrogens in women with SSD.
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Affiliation(s)
- Bodyl A Brand
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK.
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht (UMCU), Utrecht University, Utrecht, The Netherlands.
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
| | - Janna N de Boer
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht (UMCU), Utrecht University, Utrecht, The Netherlands
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands
- Center for Young Children, Karakter Child and Adolescent Psychiatry, Nijmegen, The Netherlands
| | - Elske J M Willemse
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands
| | - Cynthia S Weickert
- Neuroscience Research Australia, Sydney, NSW, Australia
- Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, Australia
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Iris E Sommer
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht (UMCU), Utrecht University, Utrecht, The Netherlands
- Department of Biomedical Sciences and Systems, Cognitive Neurosciences, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands
| | - Thomas W Weickert
- Neuroscience Research Australia, Sydney, NSW, Australia
- Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, Australia
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
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Singh AK, Pathak U, Kaur P, Dhakad R. Meditation as a Therapy or a Threat: A Case Series. Cureus 2024; 16:e75201. [PMID: 39759685 PMCID: PMC11700372 DOI: 10.7759/cureus.75201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2024] [Indexed: 01/07/2025] Open
Abstract
Meditation is an approach to self-regulate the emotions. Meditation has a beneficial effect on both physical and mental health. Various forms of meditation practices prevail in many religions and cultures for human well-being. Although meditation has so many positive effects, very few people experience negative too. Meditation-induced psychosis has been reported in the past. Here, we present a case series of seven cases who developed psychiatric illness after meditation.
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Affiliation(s)
- Amrendra K Singh
- Department of Psychiatry, Atal Bihari Vajpayee Government Medical College, Rewa, IND
| | - Umesh Pathak
- Department of Psychiatry, Birsa Munda Government Medical College, Shahdol, Shahdol, IND
| | - Partik Kaur
- Department of Psychiatry, MGM Medical College, Indore, Indore, IND
| | - Rashmi Dhakad
- Department of Psychiatry, MGM Medical College, Indore, Indore, IND
- Department of Psychiatry, Gandhi Medical College, Bhopal, Bhopal, IND
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Chen W, Xu C, Wu W, Li W, Huang W, Li Z, Li X, Xie G, Li X, Zhang C, Liang J. Differences of regional homogeneity and cognitive function between psychotic depression and drug-naïve schizophrenia. BMC Psychiatry 2024; 24:835. [PMID: 39567972 PMCID: PMC11577850 DOI: 10.1186/s12888-024-06283-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 11/11/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Psychotic depression (PD) and schizophrenia (SCZ) share overlapping symptoms yet differ in etiology, progression, and treatment approaches. Differentiating these disorders through symptom-based diagnosis is challenging, emphasizing the need for a clearer understanding of their distinct cognitive and neural mechanisms. AIM This study aims to compare cognitive impairments and brain functional activities in PD and SCZ to pinpoint distinguishing characteristics of each disorder. METHODS We evaluated cognitive function in 42 PD and 30 SCZ patients using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and resting-state functional magnetic resonance imaging (rs-fMRI). Regional homogeneity (ReHo) values were derived from rs-fMRI data, and group differences in RBANS scores were analyzed. Additionally, Pearson correlation analysis was performed to assess the relationship between cognitive domains and brain functional metrics. RESULTS (1) The SCZ group showed significantly lower RBANS scores than the PD group across all cognitive domains, particularly in visuospatial/constructional ability and delayed memory (p < 0.05); (2) The SCZ group exhibited a significantly higher ReHo value in the left precuneus compared to the PD group (p < 0.05); (3) A negative correlation was observed between visuospatial construction, delayed memory scores, and the ReHo value of the left precuneus. CONCLUSION Cognitive impairment is more pronounced in SCZ than in PD, with marked deficits in visuospatial and memory domains. Enhanced left precuneus activity further differentiates SCZ from PD and correlates with cognitive impairments in both disorders, providing neuroimaging-based evidence to aid differential diagnosis and insights into cognitive dysfunction mechanisms, while also paving a clearer path for psychiatric research.
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Affiliation(s)
- Wensheng Chen
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China
| | - Caixia Xu
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China
| | - Weibin Wu
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China
| | - Wenxuan Li
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China
| | - Wei Huang
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China
| | - Zhijian Li
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China
| | - Xiaoling Li
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China
| | - Guojun Xie
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China
| | - Xuesong Li
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China
| | - Chunguo Zhang
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China.
| | - Jiaquan Liang
- Department of Psychiatry, The Third People's Hospital of Foshan, Guangdong, 528000, People's Republic of China.
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Preller KH, Scholpp J, Wunder A, Rosenbrock H. Neuroimaging Biomarkers for Drug Discovery and Development in Schizophrenia. Biol Psychiatry 2024; 96:666-673. [PMID: 38272287 DOI: 10.1016/j.biopsych.2024.01.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/19/2023] [Accepted: 01/14/2024] [Indexed: 01/27/2024]
Abstract
Schizophrenia is a chronic mental illness that affects up to 1% of the population. While efficacious therapies are available for positive symptoms, effective treatment of cognitive and negative symptoms remains an unmet need after decades of research. New developments in the field of neuroimaging are accelerating our knowledge gain regarding the underlying pathophysiology of symptoms in schizophrenia and psychosis spectrum disorders, inspiring new targets for drug development. However, no validated and qualified biomarkers are currently available to support the development of new therapeutics. This review summarizes the current use of neuroimaging technology in clinical drug development for psychotic disorders. As exemplified by drug development programs that target NMDA receptor hypofunction, neuroimaging results play a critical role in target discovery and establishing target engagement and dose selection. Furthermore, pharmacological neuroimaging may provide response biomarkers that allow for early decision making in proof-of-concept studies that leverage pharmacological challenge models in healthy volunteers. That said, while response and predictive biomarkers are starting to be evaluated in patient populations, they continue to play a limited role. Novel approaches to neuroimaging data acquisition and analysis may aid the establishment of biomarkers that are predictive at the individual level in the future. Nevertheless, various gaps in knowledge need to be addressed and biomarkers need to be validated to establish them as "fit for purpose" in drug development.
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Affiliation(s)
- Katrin H Preller
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland.
| | - Joachim Scholpp
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Andreas Wunder
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Holger Rosenbrock
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
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Wei Y, Su W, Zhang T, Webler R, Tang X, Zheng Y, Tang Y, Xu L, Cui H, Zhu J, Qian Z, Ju M, Long B, Zhao J, Chen C, Zeng L, Zhang T, Wang J. Structural and functional abnormalities across clinical stages of psychosis: A multimodal neuroimaging investigation. Asian J Psychiatr 2024; 99:104153. [PMID: 39047353 DOI: 10.1016/j.ajp.2024.104153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 06/27/2024] [Accepted: 07/04/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND Structural and functional neurobiological abnormalities have been observed in schizophrenia. Previous studies have concentrated on specific illness stages, obscuring relationships between functional/structural changes and disorder progression. The present study aimed to quantify structural and functional abnormalities across different clinical stages using functional near-infrared spectroscopy (fNIRS) and structural magnetic resonance imaging (sMRI). METHODS Fifty-four participants with first-episode schizophrenia (FES), 120 with clinically high risk of psychosis (CHR), and 111 healthy controls (HCs) underwent functional near-infrared spectroscopy (fNIRS) to measure oxyhemoglobin (Oxy-Hb) during the verbal fluency task. Among them, 28FES, 64CHR and 55HC also finished sMRI. Oxy-Hb and gray matter volume (GMV) were compared among the three groups while controlling for covariates, including age, sex, years of education, and task performance. Mediation analysis was utilized to determine the mediating effect of GMV on Oxy-Hb and cognition. RESULTS Compared with the HC group, CHR and FES groups showed significantly reduced brain activity. However, there were no significant differences between the FES and CHR. Pronounced GMV increase in the right frontal pole area (F = 4.234, p = 0.016) was identified in the CHR and FES groups. Mediation analysis showed a significant mediation effect of the right frontal pole GMV between Channel 31 Oxy-Hb and processing speed (z = 2.105, p = 0.035) and attention/vigilance (z = 1.992, p = 0.046). CONCLUSIONS Brain activation and anatomical deficits were observed in different brain regions, suggesting that anatomical and functional abnormalities are dissociated in the early stages of psychosis. The relationship between neural activity and anatomy may reflect a specific pathophysiology related to cognitive deterioration in schizophrenia.
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Affiliation(s)
- Yanyan Wei
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Wenjun Su
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Tingyu Zhang
- Shanghai Center for Brain Science and Brain-Inspired Technology, Shanghai, China
| | - Ryan Webler
- Center for Brain Circuit Therapeutics, Brigham & Women's Hospital, Boston, MA, United States; Department of Psychiatry, Harvard Medical School, United States
| | - Xiaochen Tang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yuchen Zheng
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yingying Tang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Lihua Xu
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Huiru Cui
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Junjuan Zhu
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Zhenying Qian
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Mingliang Ju
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Bin Long
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Jian Zhao
- Department of Micro/Nano Electronics, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Cheng Chen
- Department of Micro/Nano Electronics, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Lingyun Zeng
- Department of Psychiatric Rehabilitation, Shenzhen Kangning Hospital, ShenZhen, China
| | - Tianhong Zhang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
| | - Jijun Wang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
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Suchanecka A, Boroń A, Chmielowiec K, Strońska-Pluta A, Masiak J, Lachowicz M, Chmielowiec J, Trybek G, Grzywacz A. HINT1 Gene Polymorphisms, Smoking Behaviour, and Personality Traits: A Haplotype Case-Control Study. Int J Mol Sci 2024; 25:7657. [PMID: 39062900 PMCID: PMC11276624 DOI: 10.3390/ijms25147657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 07/04/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
The factors influencing the development and maintenance of nicotine dependence are numerous and complex. Recent studies indicate that smokers exhibit distinct genetic predispositions to nicotine dependence. We aimed to analyse (1) the association between rs2551038 and cigarette smoking, (2) the association of between the rs3864236-rs2526303-rs2551038 haplotype and cigarette smoking, and (3) the personality traits measured by the NEO Five-Factor Inventory in cigarette users and never-smokers. No significant differences were present in the frequency of rs2551038 genotypes and alleles in the studied cigarette users compared to the control group. Cigarette users, compared to the control group, had higher scores on the NEO-FFI Extraversion scale (p = 0.0011), and lower scores were obtained by the cigarette users for the NEO-FFI Openness (p = 0.0060), Agreeability (p ≤ 0.000), and Conscientiousness (p ≤ 0.000) scales. There was a significant positive Pearson's linear correlation between the age and the Fagestrom test (r = 0.346; p < 0.0001) and the NEO-FFI Openness scale (r = 0.180; p < 0.0001) in the group of cigarette users. We observed significant linkage disequilibrium between rs2526303 and rs3864236 (D' = 0.3581; p < 2.2204 × 10-16) and between rs2526303 and rs2551038 (D' = 0.9993; p < 2.2204 × 10-16) in the tested sample. The sex-stratified haplotype analysis revealed that in the group of male never-smokers, the GTC haplotype was significantly more frequent than in the group of cigarette users (38% vs. 22%; p = 0.0039). The presented study reveals significant differences in personality trait scores between cases and controls. Moreover, the sex-stratified analysis showed significant differences in haplotype distribution. These results underscore the interplay between genetic predisposition, sex, and personality in nicotine-using individuals.
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Affiliation(s)
- Aleksandra Suchanecka
- Independent Laboratory of Behavioural Genetics and Epigenetics, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland; (A.S.); (A.S.-P.)
| | - Agnieszka Boroń
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland;
| | - Krzysztof Chmielowiec
- Department of Hygiene and Epidemiology, Collegium Medicum, University of Zielona Góra, 28 Zyty St., 65-046 Zielona Góra, Poland; (K.C.); (J.C.)
| | - Aleksandra Strońska-Pluta
- Independent Laboratory of Behavioural Genetics and Epigenetics, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland; (A.S.); (A.S.-P.)
| | - Jolanta Masiak
- Second Department of Psychiatry and Psychiatric Rehabilitation, Medical University of Lublin, 1 Głuska St., 20-059 Lublin, Poland;
| | - Milena Lachowicz
- Department of Psychology, Gdansk University of Physical Education and Sport, 80-336 Gdansk, Poland;
| | - Jolanta Chmielowiec
- Department of Hygiene and Epidemiology, Collegium Medicum, University of Zielona Góra, 28 Zyty St., 65-046 Zielona Góra, Poland; (K.C.); (J.C.)
| | - Grzegorz Trybek
- Department of Oral Surgery, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland;
| | - Anna Grzywacz
- Independent Laboratory of Behavioural Genetics and Epigenetics, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland; (A.S.); (A.S.-P.)
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Nourbakhsh S, Ferrando SJ. Primary versus secondary psychosis in a patient with congenital liver disease. BMJ Case Rep 2024; 17:e259623. [PMID: 38960424 PMCID: PMC11227732 DOI: 10.1136/bcr-2024-259623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2024] [Indexed: 07/05/2024] Open
Abstract
In this article we report the case of a man with congenital liver disease who later developed psychotic illness and was diagnosed with schizophrenia. We illustrate how decompensation in liver function was associated with the exacerbation of psychotic symptoms. We discuss differential diagnostic challenges, and the possible overlapping neuropathology in these two conditions that may converge on glutamate/N-methyl-D-aspartate dysfunction. This patient's case underscores the need for further research to elucidate the possible underlying mechanisms linking congenital liver disease and psychosis.
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Affiliation(s)
- Sormeh Nourbakhsh
- Psychiatry, Westchester Medical Center, Valhalla, New York, USA
- New York Medical College, Valhalla, New York, USA
| | - Stephen J Ferrando
- Westchester Medical Center Health Network, Valhalla, New York, USA
- New York Medical College School of Medicine, Valhalla, New York, USA
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10
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Chen YZ, Zhu XM, Lv P, Hou XK, Pan Y, Li A, Du Z, Xuan JF, Guo X, Xing JX, Liu K, Yao J. Association of histone modification with the development of schizophrenia. Biomed Pharmacother 2024; 175:116747. [PMID: 38744217 DOI: 10.1016/j.biopha.2024.116747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/06/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024] Open
Abstract
Schizophrenia, influenced by genetic and environmental factors, may involve epigenetic alterations, notably histone modifications, in its pathogenesis. This review summarizes various histone modifications including acetylation, methylation, phosphorylation, ubiquitination, serotonylation, lactylation, palmitoylation, and dopaminylation, and their implications in schizophrenia. Current research predominantly focuses on histone acetylation and methylation, though other modifications also play significant roles. These modifications are crucial in regulating transcription through chromatin remodeling, which is vital for understanding schizophrenia's development. For instance, histone acetylation enhances transcriptional efficiency by loosening chromatin, while increased histone methyltransferase activity on H3K9 and altered histone phosphorylation, which reduces DNA affinity and destabilizes chromatin structure, are significant markers of schizophrenia.
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Affiliation(s)
- Yun-Zhou Chen
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Xiu-Mei Zhu
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Peng Lv
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Xi-Kai Hou
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Ying Pan
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Ang Li
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Zhe Du
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Jin-Feng Xuan
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Xiaochong Guo
- Laboratory Animal Center, China Medical University, PR China
| | - Jia-Xin Xing
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China.
| | - Kun Liu
- Key Laboratory of Health Ministry in Congenital Malformation, Shengjing Hospital of China Medical University, PR China.
| | - Jun Yao
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China.
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11
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Speranza L, Molinari M, Volpicelli F, Lacivita E, Leopoldo M, Pulcrano S, Carlo Bellenchi G, Perrone Capano C, Crispino M. Modulation of neuronal morphology by antipsychotic drug: Involvement of serotonin receptor 7. Brain Res 2024; 1830:148815. [PMID: 38387714 DOI: 10.1016/j.brainres.2024.148815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/26/2024] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
Antipsychotic drugs (APDs) are the primary pharmacological treatment for schizophrenia, a complex disorder characterized by altered neuronal connectivity. Atypical or second-generation antipsychotics, such as Risperidone (RSP) and Clozapine (CZP) predominantly block dopaminergic D2 and serotonin receptor 2A (5-HT2A) neurotransmission. Both compounds also exhibit affinity for the 5-HT7R, with RSP acting as an antagonist and CZP as an inverse agonist. Our study aimed to determine whether RSP and CZP can influence neuronal morphology through a 5-HT7R-mediated mechanism. Here, we demonstrated that CZP promotes neurite outgrowth of early postnatal cortical neurons, and the 5-HT7R mediates its effect. Conversely, RSP leads to a reduction of neurite length of early postnatal cortical neurons, in a 5-HT7R-independent way. Furthermore, we found that the effects of CZP, mediated by 5-HT7R activation, require the participation of ERK and Cdk5 kinase pathways. At the same time, the modulation of neurite length by RSP does not involve these pathways. In conclusion, our findings provide valuable insights into the morphological changes induced by these two APDs in neurons and elucidate some of the associated molecular pathways. Investigating the 5-HT7R-dependent signaling pathways underlying the neuronal morphogenic effects of APDs may contribute to the identification of novel targets for the treatment of schizophrenia.
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Affiliation(s)
- Luisa Speranza
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | - Marta Molinari
- Telethon Institute of Genetics & Medicine, Via Campi Flegrei, 34, 80078 Pozzuoli, Naples, Italy
| | - Floriana Volpicelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy.
| | - Enza Lacivita
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, 70125 Bari, Italy
| | - Marcello Leopoldo
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, 70125 Bari, Italy
| | - Salvatore Pulcrano
- Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131 Naples, Italy
| | - Gian Carlo Bellenchi
- Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131 Naples, Italy
| | - Carla Perrone Capano
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | - Marianna Crispino
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
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12
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Johnson J. Effect of emotions on learning, memory, and disorders associated with the changes in expression levels: A narrative review. Brain Circ 2024; 10:134-144. [PMID: 39036298 PMCID: PMC11259327 DOI: 10.4103/bc.bc_86_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 03/13/2024] [Accepted: 03/25/2024] [Indexed: 07/23/2024] Open
Abstract
Emotions, in general, have no scientific definition. Emotions can be denoted as the mental state because of the neurophysiological changes. Emotions are related to mood, personality, temperament, and consciousness. People exhibit different emotions in different situations causing changes in cognitive functions. One of the major cognitive functions is the ability to learn, to store the acquired information in the parts of the brain such as the hippocampus, amygdala, cortex, and cerebellum. Learning and memory are affected by different types of emotions. Emotional responses such as fear, depression, and stress have impaired effects on cognitive functions such as learning and memory, whereas optimistic and happy emotions have positive effects on long-term memory. Certain disorders have greater effects on the regions of the brain which are also associated with synaptic plasticity and Learning and Memory(LM). Neuroimaging techniques are involved in studying the changing regions of the brain due to varied emotions and treatment strategies based on the changes observed. There are many drugs, and in advancements, nanotechnology is also utilized in the treatment of such psychiatric disorders. To improve mental health and physical health, emotional balance is most important, and effective care should be provided for people with less emotional quotient and different types of disorders to inhibit cognitive dysfunctions. In this review, emotions and their varied effects on a cognitive function named learning and memory, disorders associated with the defects of learning due to emotional instability, the areas of the brain that are in control of emotions, diagnosis, and treatment strategies for psychiatric disorders dependent on emotions are discussed.
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Affiliation(s)
- Jaivarsini Johnson
- Department of Medical Nanotechnology, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, Tamil Nadu, India
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13
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Ishibashi T, Nobukawa S, Tobe M, Kikuchi M, Takahashi T. Alterations in the hub structure of whole-brain functional networks in patients with drug-naïve schizophrenia: Insights from electroencephalography-based research. PCN REPORTS : PSYCHIATRY AND CLINICAL NEUROSCIENCES 2024; 3:e164. [PMID: 38868477 PMCID: PMC11114440 DOI: 10.1002/pcn5.164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 11/27/2023] [Accepted: 12/11/2023] [Indexed: 06/14/2024]
Abstract
Aim This study aimed to identify atypical hubs in the whole-brain networks of patients with schizophrenia (SZ) and examine the effects of antipsychotic medications, using electroencephalography (EEG) data. Methods We estimated the functional connectivity across all electrodes by applying the phase lag index to the EEG signals of 21 drug-naïve patients with SZ and 31 age-matched healthy controls. Betweenness centrality (BC), a measure of hub status, was calculated for each electrode and frequency band. Data from 14 patients were re-evaluated after initiating treatment with antipsychotic medications. Results BC values decreased significantly at the Fz site in the beta band, decreased significantly at Pz in the gamma band, and increased significantly at O1 in the gamma band among patients with SZ. These changes persisted after antipsychotic treatment and were unrelated to clinical symptoms. Conclusion The abnormal hub topology we observed, especially in the high-frequency band, may reflect the pathophysiology of SZ, and this study highlights the utility of BC analysis of EEG data for detecting alterations in the whole-brain networks of patients with SZ.
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Affiliation(s)
| | - Sou Nobukawa
- Department of Computer ScienceChiba Institute of TechnologyChibaJapan
- Graduate School of Information and Computer ScienceChiba Institute of TechnologyChibaJapan
- Research Center for Mathematical EngineeringChiba Institute of TechnologyChibaJapan
- Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental HealthNational Center of Neurology and PsychiatryTokyoJapan
| | - Mayuna Tobe
- Graduate School of Information and Computer ScienceChiba Institute of TechnologyChibaJapan
| | - Mitsuru Kikuchi
- Department of Psychiatry & Behavioral ScienceKanazawa UniversityIshikawaJapan
- Research Center for Child Mental DevelopmentKanazawa UniversityIshikawaJapan
| | - Tetsuya Takahashi
- Department of NeuropsychiatryUniversity of FukuiFukuiJapan
- Research Center for Child Mental DevelopmentKanazawa UniversityIshikawaJapan
- Uozu Shinkei SanatoriumUozuJapan
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14
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Lv Y, Wen L, Hu WJ, Deng C, Ren HW, Bao YN, Su BW, Gao P, Man ZY, Luo YY, Li CJ, Xiang ZX, Wang B, Luan ZL. Schizophrenia in the genetic era: a review from development history, clinical features and genomic research approaches to insights of susceptibility genes. Metab Brain Dis 2024; 39:147-171. [PMID: 37542622 DOI: 10.1007/s11011-023-01271-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 07/27/2023] [Indexed: 08/07/2023]
Abstract
Schizophrenia is a devastating neuropsychiatric disorder affecting 1% of the world population and ranks as one of the disorders providing the most severe burden for society. Schizophrenia etiology remains obscure involving multi-risk factors, such as genetic, environmental, nutritional, and developmental factors. Complex interactions of genetic and environmental factors have been implicated in the etiology of schizophrenia. This review provides an overview of the historical origins, pathophysiological mechanisms, diagnosis, clinical symptoms and corresponding treatment of schizophrenia. In addition, as schizophrenia is a polygenic, genetic disorder caused by the combined action of multiple micro-effective genes, we further detail several approaches, such as candidate gene association study (CGAS) and genome-wide association study (GWAS), which are commonly used in schizophrenia genomics studies. A number of GWASs about schizophrenia have been performed with the hope to identify novel, consistent and influential risk genetic factors. Finally, some schizophrenia susceptibility genes have been identified and reported in recent years and their biological functions are also listed. This review may serve as a summary of past research on schizophrenia genomics and susceptibility genes (NRG1, DISC1, RELN, BDNF, MSI2), which may point the way to future schizophrenia genetics research. In addition, depending on the above discovery of susceptibility genes and their exact function, the development and application of antipsychotic drugs will be promoted in the future.
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Affiliation(s)
- Ye Lv
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Lin Wen
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Wen-Juan Hu
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Chong Deng
- Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116027, China
| | - Hui-Wen Ren
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Ya-Nan Bao
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Bo-Wei Su
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Ping Gao
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Zi-Yue Man
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Yi-Yang Luo
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Cheng-Jie Li
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Zhi-Xin Xiang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Bing Wang
- Department of Endocrinology and Metabolism, The Central hospital of Dalian University of Technology, Dalian, 116000, China.
| | - Zhi-Lin Luan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China.
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15
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Zuccoli GS, Nascimento JM, Moraes-Vieira PM, Rehen SK, Martins-de-Souza D. Mitochondrial, cell cycle control and neuritogenesis alterations in an iPSC-based neurodevelopmental model for schizophrenia. Eur Arch Psychiatry Clin Neurosci 2023; 273:1649-1664. [PMID: 37039888 DOI: 10.1007/s00406-023-01605-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 03/29/2023] [Indexed: 04/12/2023]
Abstract
Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1% of the world's population. Proteomic studies and other approaches have provided evidence of compromised cellular processes in the disorder, including mitochondrial function. Most of the studies so far have been conducted on postmortem brain tissue from patients, and therefore, do not allow the evaluation of the neurodevelopmental aspect of the disorder. To circumvent that, we studied the mitochondrial and nuclear proteomes of neural stem cells (NSCs) and neurons derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients versus healthy controls to assess possible alterations related to energy metabolism and mitochondrial function during neurodevelopment in the disorder. Our results revealed differentially expressed proteins in pathways related to mitochondrial function, cell cycle control, DNA repair and neuritogenesis and their possible implication in key process of neurodevelopment, such as neuronal differentiation and axonal guidance signaling. Moreover, functional analysis of NSCs revealed alterations in mitochondrial oxygen consumption in schizophrenia-derived cells and a tendency of higher levels of intracellular reactive oxygen species (ROS). Hence, this study shows evidence that alterations in important cellular processes are present during neurodevelopment and could be involved with the establishment of schizophrenia, as well as the phenotypic traits observed in adult patients. Neural stem cells (NSCs) and neurons were derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients and controls. Proteomic analyses were performed on the enriched mitochondrial and nuclear fractions of NSCs and neurons. Whole-cell proteomic analysis was also performed in neurons. Our results revealed alteration in proteins related to mitochondrial function, cell cycle control, among others. We also performed energy pathway analysis and reactive oxygen species (ROS) analysis of NSCs, which revealed alterations in mitochondrial oxygen consumption and a tendency of higher levels of intracellular ROS in schizophrenia-derived cells.
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Affiliation(s)
- Giuliana S Zuccoli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Juliana M Nascimento
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
- D'Or Institute for Research and Education (IDOR), São Paulo, Brazil
| | - Pedro M Moraes-Vieira
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil
- Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, SP, 13083-862, Brazil
- Obesity and Comorbidities Research Center (OCRC), University of Campinas, São Paulo, Brazil
| | - Stevens K Rehen
- D'Or Institute for Research and Education (IDOR), São Paulo, Brazil
- Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Daniel Martins-de-Souza
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil.
- D'Or Institute for Research and Education (IDOR), São Paulo, Brazil.
- Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, SP, 13083-862, Brazil.
- Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Científico e Tecnológico, São Paulo, Brazil.
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Ju S, Shin Y, Han S, Kwon J, Choi TG, Kang I, Kim SS. The Gut-Brain Axis in Schizophrenia: The Implications of the Gut Microbiome and SCFA Production. Nutrients 2023; 15:4391. [PMID: 37892465 PMCID: PMC10610543 DOI: 10.3390/nu15204391] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
Schizophrenia, a severe mental illness affecting about 1% of the population, manifests during young adulthood, leading to abnormal mental function and behavior. Its multifactorial etiology involves genetic factors, experiences of adversity, infection, and gene-environment interactions. Emerging research indicates that maternal infection or stress during pregnancy may also increase schizophrenia risk in offspring. Recent research on the gut-brain axis highlights the gut microbiome's potential influence on central nervous system (CNS) function and mental health, including schizophrenia. The gut microbiota, located in the digestive system, has a significant role to play in human physiology, affecting immune system development, vitamin synthesis, and protection against pathogenic bacteria. Disruptions to the gut microbiota, caused by diet, medication use, environmental pollutants, and stress, may lead to imbalances with far-reaching effects on CNS function and mental health. Of interest are short-chain fatty acids (SCFAs), metabolic byproducts produced by gut microbes during fermentation. SCFAs can cross the blood-brain barrier, influencing CNS activity, including microglia and cytokine modulation. The dysregulation of neurotransmitters produced by gut microbes may contribute to CNS disorders, including schizophrenia. This review explores the potential relationship between SCFAs, the gut microbiome, and schizophrenia. Our aim is to deepen the understanding of the gut-brain axis in schizophrenia and to elucidate its implications for future research and therapeutic approaches.
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Affiliation(s)
- Songhyun Ju
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.); (Y.S.); (S.H.); (J.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Yoonhwa Shin
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.); (Y.S.); (S.H.); (J.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sunhee Han
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.); (Y.S.); (S.H.); (J.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Juhui Kwon
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.); (Y.S.); (S.H.); (J.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Tae Gyu Choi
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Insug Kang
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.); (Y.S.); (S.H.); (J.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sung Soo Kim
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.); (Y.S.); (S.H.); (J.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
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17
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Yadav J, Bhardwaj A, Jangid P, Singh P, Gupta R. Meditation-A Slippery Slope for Psychosis: A Case Series With Review of Evidence. J Nerv Ment Dis 2023; 211:634-638. [PMID: 37505896 DOI: 10.1097/nmd.0000000000001656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/30/2023]
Abstract
ABSTRACT The practice of meditation has been traditionally viewed as a self-regulatory approach that aids in psychological well-being. Over the last decade, mindfulness-based meditation has gained a separate therapeutic significance in various mental health conditions. There has also been considerable understanding of the adverse effects of meditation over the years. Despite this, there is still underreporting of the altered behavioral presentations arising possibly because of intensive and unguided meditation practices. We present two cases of meditation-related psychosis with different clinical presentations. The write-up highlights the need for tailoring the meditation practices after evaluation of mental state of the individuals and early detection of "at-risk" mental states. There should be regular screening of emergence of any unwanted effects during the course of meditation and the guides should be able to detect the early warning signs of psychosis.
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Affiliation(s)
- Jagriti Yadav
- Department of Psychiatry, Institute of Mental Health, Pt B. D. Sharma University of Health Sciences, Rohtak, Haryana
| | - Akansha Bhardwaj
- Department of Psychiatry, Hamdard Institute of Medical Sciences & Research, New Delhi
| | - Purushottam Jangid
- Institute of Mental Health, Pt B. D. Sharma University of Health Sciences, Rohtak, Haryana, India
| | - Priti Singh
- Institute of Mental Health, Pt B. D. Sharma University of Health Sciences, Rohtak, Haryana, India
| | - Rajiv Gupta
- Institute of Mental Health, Pt B. D. Sharma University of Health Sciences, Rohtak, Haryana, India
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18
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Batista-Brito R, Majumdar A, Nuño A, Ward C, Barnes C, Nikouei K, Vinck M, Cardin JA. Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics. Mol Psychiatry 2023; 28:3133-3143. [PMID: 37069344 PMCID: PMC10618960 DOI: 10.1038/s41380-023-02066-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/28/2023] [Accepted: 04/03/2023] [Indexed: 04/19/2023]
Abstract
GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as a powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.
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Affiliation(s)
- Renata Batista-Brito
- Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave, The Bronx, NY, 10461, USA.
- Department of Neuroscience, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA.
- Department of Psychiatry and Behavioral Sciences, Einstein College of Medicine, 1300 Morris Park Ave, The Bronx, NY, 10461, USA.
- Department of Genetics, Einstein College of Medicine, 1300 Morris Park Ave, The Bronx, NY, 10461, USA.
| | - Antara Majumdar
- Department of Neuroscience, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA
- Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Road, Oxford, OX1 3PT, England
| | - Alejandro Nuño
- Department of Neuroscience, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA
| | - Claire Ward
- Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave, The Bronx, NY, 10461, USA
| | - Clayton Barnes
- Department of Neuroscience, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA
| | - Kasra Nikouei
- Department of Neuroscience, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Martin Vinck
- Department of Neuroscience, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA
- Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Deutschordenstraße 46, 60528, Frankfurt, Germany
| | - Jessica A Cardin
- Department of Neuroscience, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA.
- Kavli Institute of Neuroscience, Yale University, 333 Cedar St., New Haven, CT, 06520, USA.
- Wu Tsai Institute, Yale University, 100 College St., New Haven, CT, 06520, USA.
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19
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Mekiten O, Yitzhaky A, Gould N, Rosenblum K, Hertzberg L. Ribosome subunits are upregulated in brain samples of a subgroup of individuals with schizophrenia: A systematic gene expression meta-analysis. J Psychiatr Res 2023; 164:372-381. [PMID: 37413782 DOI: 10.1016/j.jpsychires.2023.06.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 06/05/2023] [Accepted: 06/15/2023] [Indexed: 07/08/2023]
Abstract
One of the new theories accounting for the underlying pathophysiology of schizophrenia is excitation/inhibition imbalance. Interestingly, perturbation in protein synthesis machinery as well as oxidative stress can lead to excitation/inhibition imbalance. We thus performed a systematic meta-analysis of the expression of 79 ribosome subunit genes and two oxidative-stress related genes, HIF1A and NQO1, in brain samples of individuals with schizophrenia vs. healthy controls. We integrated 12 gene expression datasets, following the PRISMA guidelines (overall 511 samples, 253 schizophrenia and 258 controls). Five ribosome subunit genes were significantly upregulated in a subgroup of the patients with schizophrenia, while 24 (30%) showed a tendency for upregulation. HIF1A and NQO1 were also found to be significantly upregulated. Moreover, HIF1A and NQO1 showed positive correlation with the expression of the upregulated ribosome subunit genes. Our results, together with previous findings, suggest a possible role for altered mRNA translation in the pathogenesis of schizophrenia, in association with markers of increased oxidative stress in a subgroup of patients. Further studies should define whether the upregulation of ribosome subunits result in altered mRNA translation, which proteins are modulated and how it characterizes a subgroup of the patients with schizophrenia.
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Affiliation(s)
- Ori Mekiten
- Faculty of Medicine, Tel-Aviv University, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Nathaniel Gould
- Sagol Department of Neurobiology, University of Haifa, Haifa, Israel
| | - Kobi Rosenblum
- Sagol Department of Neurobiology, University of Haifa, Haifa, Israel; Center for Gene Manipulation in the Brain, University of Haifa, Haifa, Israel
| | - Libi Hertzberg
- Faculty of Medicine, Tel-Aviv University, Israel; Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel; Shalvata Mental Health Center, Israel.
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20
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Hou MR, Wang J, Xue JH, Pei JQ, Shi Y, Li XW. Gender differences among long-stay inpatients with schizophrenia in China: A cross-sectional study. Heliyon 2023; 9:e15719. [PMID: 37159715 PMCID: PMC10163644 DOI: 10.1016/j.heliyon.2023.e15719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 04/03/2023] [Accepted: 04/19/2023] [Indexed: 05/11/2023] Open
Abstract
Objective We sought to examine the independent correlates of long-term hospitalization in a sample of Chinese inpatients with schizophrenia (SCZ) from a gender-based perspective. Methods This was a cross-sectional study that was carried out in a tertiary psychiatric hospital. All adult inpatients in this hospital were screened from January to March 2020, 251 of whom were identified as long-stay inpatients with SCZ (LSIS) and 224 as short-stay inpatients with SCZ (SSIS). Demographic and clinical information of the two groups was collected through medical records, scale assessments and interviews. Gender differences were analyzed, and independent correlates of long-stay between genders were explored by logistic regression analyses. Results Compared to SSIS, greater proportions of LSIS patients were male (64.1%), single (82.1%), unemployed (81.7%) and had no family caregivers (54.2%). For LSIS per se, proportionally more males were single (88.8%), had no family caregiver (65.8%), had concomitant physical disease (65.2%) and had a history of hazardous behavior (27.3%) than their female counterparts. For females, the top independent risk factors for a long stay included poor functioning (OR = 5.9, 95% CI: 2.9-12.0), older age (OR = 4.3, 95% CI: 2.1-9.1) and being single (OR = 3.9, 95% CI: 1.8-8.4). Similar to women, both older age (OR = 5.3, 95% CI: 2.5-11.2) and poor functioning (OR = 4.0, 95% CI: 2.1-7.9) were also independent factors for long-term hospitalization of male patients; however, having no family caregiver (OR = 10.2, 95% CI: 4.6-22.6) was the primary risk factor for men. Conclusions Both clinical and nonclinical factors play important roles in long-term hospitalization in Chinese patients with schizophrenia. There are overlaps and distinctions across genders with respect to the independent factors of long stays. These findings provide clues for developing better service strategies for this population, and highlight the importance of paying attention to gender differences in further research in this field.
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Affiliation(s)
- Ming-ru Hou
- Department of General Psychiatry, The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, 156 Qianrong Road, Wuxi, Jiangsu 214151, China
- School of Nursing, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Jun Wang
- Department of Clinical Psychology, The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, 156 Qianrong Road, Wuxi, Jiangsu 214151, China
- Corresponding author. Department of Clinical Psychology, The Affiliated Mental Health Center of Jiangnan University, 156 Qianrong Road, Wuxi, Jiangsu 214151, China.
| | - Jian-hua Xue
- Tongji University School of Medicine, Shanghai 200092, China
| | - Jian-qin Pei
- Department of General Psychiatry, The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, 156 Qianrong Road, Wuxi, Jiangsu 214151, China
| | - Yan Shi
- Nursing Department, Shanghai Tenth People's Hospital Affiliated to Tongji University, 301 Yanchang Road, Shanghai 200072, China
| | - Xian-wen Li
- School of Nursing, Nanjing Medical University, Nanjing, Jiangsu 211166, China
- Corresponding author. School of Nursing, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
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21
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Li Z, Qing Y, Cui G, Li M, Liu T, Zeng Y, Zhou C, Hu X, Jiang J, Wang D, Gao Y, Zhang J, Cai C, Wang T, Wan C. Shotgun metagenomics reveals abnormal short-chain fatty acid-producing bacteria and glucose and lipid metabolism of the gut microbiota in patients with schizophrenia. Schizophr Res 2023; 255:59-66. [PMID: 36965360 DOI: 10.1016/j.schres.2023.03.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 01/11/2023] [Accepted: 03/03/2023] [Indexed: 03/27/2023]
Abstract
Evidence has shown that the gut microbiota is closely related to the pathogenesis of schizophrenia, but temporal changes in the gut microbiota of patients with schizophrenia (SZ) during treatment remain unclear. Here, to evaluate temporal changes in the gut microbiota in schizophrenia, we performed whole-genome shotgun metagenomics on fecal samples from 36 healthy controls (HCs) and 19 baseline-period patients, and followed up with patients upon treatment. Compared to that in HCs, beta diversity in SZ was significantly distinct. The genera Bacteroides, Prevotella and Clostridium were the top 3 altered genera between SZ and HCs, and the Bacteroides-Prevotella ratio was significantly increased in SZ. Thirty-three percent of differentially abundant species were short-chain fatty acid (SCFA)-producing bacteria. Functional analysis showed that glucose and lipid metabolism of the gut microbiota was decreased in SZ compared with those in HCs. The abundances of two rate-limiting enzymes in glucose and lipid metabolism, phosphofructokinase (PFK) and acetyl-CoA carboxylase (ACC), were significantly decreased in SZ, and differentially abundant metabolism-related enzymes were significantly associated with SCFA-producing bacteria. Next, we found that the abundance of SCFA-producing bacteria also changed after treatment and that Clostridium was significantly negatively correlated with the total positive and negative syndrome scale (PANSS) score in patients. Functional analysis showed that glycoside hydrolase family 30 incrementally increased in abundance during treatment and were significantly associated with SCFA-producing bacteria. Our findings help to provide evidence for the role of gut microbiota in the occurrence and development of schizophrenia.
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Affiliation(s)
- Zhuyun Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Qing
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Gaoping Cui
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Minghui Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Tiantian Liu
- Department of Bioinformatics and Biostatistics, Shanghai Jiao Tong University, Shanghai, China; SJTU-Yale Joint Center for Biostatistics and Data Science, Shanghai Jiao Tong University, Shanghai, China
| | - Yanyan Zeng
- Department of Bioinformatics and Biostatistics, Shanghai Jiao Tong University, Shanghai, China; SJTU-Yale Joint Center for Biostatistics and Data Science, Shanghai Jiao Tong University, Shanghai, China
| | - Chao Zhou
- Department of Bioinformatics and Biostatistics, Shanghai Jiao Tong University, Shanghai, China; SJTU-Yale Joint Center for Biostatistics and Data Science, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaowen Hu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Jiang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Dandan Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Gao
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Juan Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Changqun Cai
- The Fourth People's Hospital of Wuhu, Wuhu, China
| | - Tao Wang
- Department of Bioinformatics and Biostatistics, Shanghai Jiao Tong University, Shanghai, China; SJTU-Yale Joint Center for Biostatistics and Data Science, Shanghai Jiao Tong University, Shanghai, China.
| | - Chunling Wan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
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22
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Nakamura T, Dinh TH, Asai M, Matsumoto J, Nishimaru H, Setogawa T, Honda S, Yamada H, Mihara T, Nishijo H. Suppressive effects of ketamine on auditory steady-state responses in intact, awake macaques: A non-human primate model of schizophrenia. Brain Res Bull 2023; 193:84-94. [PMID: 36539101 DOI: 10.1016/j.brainresbull.2022.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Auditory steady-state responses (ASSRs) are recurrent neural activities entrained to regular cyclic auditory stimulation. ASSRs are altered in individuals with schizophrenia, and may be related to hypofunction of the N-methyl-D-aspartate (NMDA) glutamate receptor. Noncompetitive NMDA receptor antagonists, including ketamine, have been used in ASSR studies of rodent models of schizophrenia. Although animal studies using non-human primates are required to complement rodent studies, the effects of ketamine on ASSRs are unknown in intact awake non-human primates. In this study, after administration of vehicle or ketamine, click trains at 20-83.3 Hz were presented to elicit ASSRs during recording of electroencephalograms in intact, awake macaque monkeys. The results indicated that ASSRs quantified by event-related spectral perturbation and inter-trial coherence were maximal at 83.3 Hz after vehicle administration, and that ketamine reduced ASSRs at 58.8 and 83.3 Hz, but not at 20 and 40 Hz. The present results demonstrated a reduction of ASSRs by the NMDA receptor antagonist at optimal frequencies with maximal responses in intact, awake macaques, comparable to ASSR reduction in patients with schizophrenia. These findings suggest that ASSR can be used as a neurophysiological biomarker of the disturbance of gamma-oscillatory neural circuits in this ketamine model of schizophrenia using intact, awake macaques. Thus, this model with ASSRs would be useful in the investigation of human brain pathophysiology as well as in preclinical translational research.
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Affiliation(s)
- Tomoya Nakamura
- System Emotional Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Department of Anatomy, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan
| | - Trong Ha Dinh
- System Emotional Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Department of Physiology, Vietnam Military Medical University, Hanoi 100000, Viet Nam
| | - Makoto Asai
- Candidate Discovery Science Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan
| | - Jumpei Matsumoto
- System Emotional Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Research Center for Idling Brain Science (RCIBS), University of Toyama, Toyama 930-0194, Japan
| | - Hiroshi Nishimaru
- System Emotional Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Research Center for Idling Brain Science (RCIBS), University of Toyama, Toyama 930-0194, Japan
| | - Tsuyoshi Setogawa
- System Emotional Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Research Center for Idling Brain Science (RCIBS), University of Toyama, Toyama 930-0194, Japan
| | - Sokichi Honda
- Candidate Discovery Science Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan
| | - Hiroshi Yamada
- Candidate Discovery Science Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan
| | - Takuma Mihara
- Candidate Discovery Science Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan
| | - Hisao Nishijo
- System Emotional Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Research Center for Idling Brain Science (RCIBS), University of Toyama, Toyama 930-0194, Japan.
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23
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Segev S, Yitzhaky A, Ben Shachar D, Hertzberg L. VDAC genes down-regulation in brain samples of individuals with schizophrenia is revealed by a systematic meta-analysis. Neurosci Res 2023:S0168-0102(23)00022-6. [PMID: 36717018 DOI: 10.1016/j.neures.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 01/23/2023] [Accepted: 01/26/2023] [Indexed: 01/29/2023]
Abstract
Mitochondrial dysfunction was shown to be involved in schizophrenia pathophysiology. Abnormal energy states can lead to alterations in neural function and thereby to the cognitive and behavioral aberrations characteristics of schizophrenia. Voltage-dependent anion-selective channels (VDAC) are located in the outer mitochondrial membrane and are involved in mitochondrial energy production. Only few studies explored VDAC genes' expression in schizophrenia, and their results were not consistent. We conducted a systematic meta-analysis of ten brain samples gene expression datasets (overall 368 samples, 179 schizophrenia, 189 controls). In addition, we conducted a meta-analysis of three blood samples datasets (overall 300 samples, 167 schizophrenia, 133 controls). Pairwise correlation analysis was conducted between the VDAC and proteasome subunit genes' expression patterns. VDAC1, VDAC2 and VDAC3 showed significant down-regulation in brain samples of patients with schizophrenia. They also showed significant positive correlations with the proteasome subunit genes' expression levels. Our findings suggest that VDAC genes might play a role in mitochondrial dysfunction in schizophrenia. VDAC1 was down-regulated also in blood samples, which suggests its potential role as a biomarker for schizophrenia. The correlation with proteasome subunits, which were previously shown to be down-regulated in a subgroup of the patients, suggests that our findings might characterize a subgroup of the patients. This direction has the potential to lead to patients' stratification and more precisely-targeted therapy and necessitates further study.
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Affiliation(s)
- Shaked Segev
- Sackler School of Medicine, Tel-Aviv University, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Dorit Ben Shachar
- Psychobiology Research Lab, Department of Neuroscience, The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Israel
| | - Libi Hertzberg
- Sackler School of Medicine, Tel-Aviv University, Israel; Shalvata Mental Health Center, Israel; Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
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24
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Tomagra G, Franchino C, Cesano F, Chiarion G, de lure A, Carbone E, Calabresi P, Mesin L, Picconi B, Marcantoni A, Carabelli V. Alpha-synuclein oligomers alter the spontaneous firing discharge of cultured midbrain neurons. Front Cell Neurosci 2023; 17:1078550. [PMID: 36744002 PMCID: PMC9896582 DOI: 10.3389/fncel.2023.1078550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/06/2023] [Indexed: 01/21/2023] Open
Abstract
The aim of this work was to monitor the effects of extracellular α-synuclein on the firing activity of midbrain neurons dissociated from substantia nigra TH-GFP mice embryos and cultured on microelectrode arrays (MEA). We monitored the spontaneous firing discharge of the network for 21 days after plating and the role of glutamatergic and GABAergic inputs in regulating burst generation and network synchronism. Addition of GABA A , AMPA and NMDA antagonists did not suppress the spontaneous activity but allowed to identify three types of neurons that exhibited different modalities of firing and response to applied L-DOPA: high-rate (HR) neurons, low-rate pacemaking (LR-p), and low-rate non-pacemaking (LR-np) neurons. Most HR neurons were insensitive to L-DOPA, while the majority of LR-p neurons responded with a decrease of the firing discharge; less defined was the response of LR-np neurons. The effect of exogenous α-synuclein (α-syn) on the firing discharge of midbrain neurons was then studied by varying the exposure time (0-48 h) and the α-syn concentration (0.3-70 μM), while the formation of α-syn oligomers was monitored by means of AFM. Independently of the applied concentration, acute exposure to α-syn monomers did not exert any effect on the spontaneous firing rate of HR, LR-p, and LR-np neurons. On the contrary, after 48 h exposure, the firing activity was drastically altered at late developmental stages (14 days in vitro, DIV, neurons): α-syn oligomers progressively reduced the spontaneous firing discharge (IC50 = 1.03 μM), impaired burst generation and network synchronism, proportionally to the increased oligomer/monomer ratio. Different effects were found on early-stage developed neurons (9 DIV), whose firing discharge remained unaltered, regardless of the applied α-syn concentration and the exposure time. Our findings unravel, for the first time, the variable effects of exogenous α-syn at different stages of midbrain network development and provide new evidence for the early detection of neuronal function impairment associated to aggregated forms of α-syn.
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Affiliation(s)
- Giulia Tomagra
- Drug Science Department, University of Torino, Turin, Italy
- Nanostructured Interfaces and Surfaces Inter-Departmental Research Centre, Turin, Italy
| | | | - Federico Cesano
- Nanostructured Interfaces and Surfaces Inter-Departmental Research Centre, Turin, Italy
- Department of Chemistry and INSTM-UdR Torino, Turin, Italy
| | - Giovanni Chiarion
- Mathematical Biology and Physiology, Department of Electronics and Telecommunications, Turin, Italy
| | - Antonio de lure
- Laboratory Experimental Neurophysiology, IRCCS San Raffaele Rome, Rome, Italy
| | - Emilio Carbone
- Drug Science Department, University of Torino, Turin, Italy
- Nanostructured Interfaces and Surfaces Inter-Departmental Research Centre, Turin, Italy
| | - Paolo Calabresi
- Neurological Clinic, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Neurology, Department of Neuroscience, Faculty of Medicine, Università Cattolica del “Sacro Cuore,”Rome, Italy
| | - Luca Mesin
- Mathematical Biology and Physiology, Department of Electronics and Telecommunications, Turin, Italy
| | - Barbara Picconi
- Laboratory Experimental Neurophysiology, IRCCS San Raffaele Rome, Rome, Italy
- Dipartimento di Scienze Umane e Promozione della Qualitá della Vita, Telematic University San Raffaele Roma, Rome, Italy
| | - Andrea Marcantoni
- Drug Science Department, University of Torino, Turin, Italy
- Nanostructured Interfaces and Surfaces Inter-Departmental Research Centre, Turin, Italy
| | - Valentina Carabelli
- Drug Science Department, University of Torino, Turin, Italy
- Nanostructured Interfaces and Surfaces Inter-Departmental Research Centre, Turin, Italy
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25
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Zoghbi AW, Lieberman JA, Girgis RR. The neurobiology of duration of untreated psychosis: a comprehensive review. Mol Psychiatry 2023; 28:168-190. [PMID: 35931757 PMCID: PMC10979514 DOI: 10.1038/s41380-022-01718-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 07/14/2022] [Accepted: 07/21/2022] [Indexed: 01/11/2023]
Abstract
Duration of untreated psychosis (DUP) is defined as the time from the onset of psychotic symptoms until the first treatment. Studies have shown that longer DUP is associated with poorer response rates to antipsychotic medications and impaired cognition, yet the neurobiologic correlates of DUP are poorly understood. Moreover, it has been hypothesized that untreated psychosis may be neurotoxic. Here, we conducted a comprehensive review of studies that have examined the neurobiology of DUP. Specifically, we included studies that evaluated DUP using a range of neurobiologic and imaging techniques and identified 83 articles that met inclusion and exclusion criteria. Overall, 27 out of the total 83 studies (32.5%) reported a significant neurobiological correlate with DUP. These results provide evidence against the notion of psychosis as structurally or functionally neurotoxic on a global scale and suggest that specific regions of the brain, such as temporal regions, may be more vulnerable to the effects of DUP. It is also possible that current methodologies lack the resolution needed to more accurately examine the effects of DUP on the brain, such as effects on synaptic density. Newer methodologies, such as MR scanners with stronger magnets, PET imaging with newer ligands capable of measuring subcellular structures (e.g., the PET ligand [11C]UCB-J) may be better able to capture these limited neuropathologic processes. Lastly, to ensure robust and replicable results, future studies of DUP should be adequately powered and specifically designed to test for the effects of DUP on localized brain structure and function with careful attention paid to potential confounds and methodological issues.
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Affiliation(s)
- Anthony W Zoghbi
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, 77030, USA.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Institute of Genomic Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA.
- Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, 10032, USA.
- Office of Mental Health, New York State Psychiatric Institute, New York, NY, 10032, USA.
| | - Jeffrey A Lieberman
- Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, 10032, USA
| | - Ragy R Girgis
- Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, 10032, USA.
- Office of Mental Health, New York State Psychiatric Institute, New York, NY, 10032, USA.
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26
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Kuo CY, Lin CH, Lane HY. Targeting D-Amino Acid Oxidase (DAAO) for the Treatment of Schizophrenia: Rationale and Current Status of Research. CNS Drugs 2022; 36:1143-1153. [PMID: 36194364 DOI: 10.1007/s40263-022-00959-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/14/2022] [Indexed: 11/29/2022]
Abstract
In the brain, D-amino acid oxidase (DAAO) is a peroxisomal flavoenzyme. Through oxidative deamination by DAAO, D-serine, the main coagonist of synaptic N-methyl-D-aspartate receptors (NMDARs), is degraded into α-keto acids and ammonia; flavin adenine dinucleotide (FAD) is simultaneously reduced to dihydroflavine-adenine dinucleotide (FADH2), which is subsequently reoxidized to FAD, with hydrogen peroxide produced as a byproduct. NMDAR hypofunction is implicated in the pathogenesis of schizophrenia. In previous studies, compared with control subjects, patients with schizophrenia had lower D-serine levels in peripheral blood and cerebrospinal fluid but higher DAAO expression and activity in the brain. Inhibiting DAAO activity and slowing D-serine degradation by using DAAO inhibitors to enhance NMDAR function may be a new strategy for use in the treatment of schizophrenia. The aim of this leading article is to review the current research in DAAO inhibitors.
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Affiliation(s)
- Chien-Yi Kuo
- Department of Psychiatry, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung City, 404327, Taiwan, ROC.,Graduate Institute of Biomedical Sciences, China Medical University, No. 91, Xueshi Rd., North Dis., Taichung City, 404333, Taiwan, ROC
| | - Chieh-Hsin Lin
- Graduate Institute of Biomedical Sciences, China Medical University, No. 91, Xueshi Rd., North Dis., Taichung City, 404333, Taiwan, ROC. .,Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist., Kaohsiung City, 83301, Taiwan, ROC. .,School of Medicine, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan, ROC.
| | - Hsien-Yuan Lane
- Department of Psychiatry, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung City, 404327, Taiwan, ROC. .,Graduate Institute of Biomedical Sciences, China Medical University, No. 91, Xueshi Rd., North Dis., Taichung City, 404333, Taiwan, ROC. .,Department of Psychology, College of Medical and Health Sciences, Asia University, No. 500, Lioufeng Rd., Wufeng Dist., Taichung City, 413305, Taiwan, ROC.
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27
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Dienel SJ, Schoonover KE, Lewis DA. Cognitive Dysfunction and Prefrontal Cortical Circuit Alterations in Schizophrenia: Developmental Trajectories. Biol Psychiatry 2022; 92:450-459. [PMID: 35568522 PMCID: PMC9420748 DOI: 10.1016/j.biopsych.2022.03.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/28/2022] [Accepted: 03/04/2022] [Indexed: 01/01/2023]
Abstract
Individuals with schizophrenia (SZ) exhibit cognitive performance below expected levels based on familial cognitive aptitude. One such cognitive process, working memory (WM), is robustly impaired in SZ. These WM impairments, which emerge over development during the premorbid and prodromal stages of SZ, appear to reflect alterations in the neural circuitry of the dorsolateral prefrontal cortex. Within the dorsolateral prefrontal cortex, a microcircuit formed by reciprocal connections between excitatory layer 3 pyramidal neurons and inhibitory parvalbumin basket cells (PVBCs) appears to be a key neural substrate for WM. Postmortem human studies indicate that both layer 3 pyramidal neurons and PVBCs are altered in SZ, suggesting that levels of excitation and inhibition are lower in the microcircuit. Studies in monkeys indicate that features of both cell types exhibit distinctive postnatal developmental trajectories. Together, the results of these studies suggest a model in which 1) genetic and/or early environmental insults to excitatory signaling in layer 3 pyramidal neurons give rise to cognitive impairments during the prodromal phase of SZ and evoke compensatory changes in inhibition that alter the developmental trajectories of PVBCs, and 2) synaptic pruning during adolescence further lowers excitatory activity to a level that exceeds the compensatory capacity of PVBC inhibition, leading to a failure of the normal maturational improvements in WM during the prodromal and early clinical stages of SZ. Findings that support as well as challenge this model are discussed.
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Affiliation(s)
- Samuel J Dienel
- Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neuroscience, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania
| | - Kirsten E Schoonover
- Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - David A Lewis
- Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neuroscience, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania.
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Buck SA, Quincy Erickson-Oberg M, Logan RW, Freyberg Z. Relevance of interactions between dopamine and glutamate neurotransmission in schizophrenia. Mol Psychiatry 2022; 27:3583-3591. [PMID: 35681081 PMCID: PMC9712151 DOI: 10.1038/s41380-022-01649-w] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/16/2022] [Accepted: 05/25/2022] [Indexed: 02/08/2023]
Abstract
Dopamine (DA) and glutamate neurotransmission are strongly implicated in schizophrenia pathophysiology. While most studies focus on contributions of neurons that release only DA or glutamate, neither DA nor glutamate models alone recapitulate the full spectrum of schizophrenia pathophysiology. Similarly, therapeutic strategies limited to either system cannot effectively treat all three major symptom domains of schizophrenia: positive, negative, and cognitive symptoms. Increasing evidence suggests extensive interactions between the DA and glutamate systems and more effective treatments may therefore require the targeting of both DA and glutamate signaling. This offers the possibility that disrupting DA-glutamate circuitry between these two systems, particularly in the striatum and forebrain, culminate in schizophrenia pathophysiology. Yet, the mechanisms behind these interactions and their contributions to schizophrenia remain unclear. In addition to circuit- or system-level interactions between neurons that solely release either DA or glutamate, here we posit that functional alterations involving a subpopulation of neurons that co-release both DA and glutamate provide a novel point of integration between DA and glutamate systems, offering a key missing link in our understanding of schizophrenia pathophysiology. Better understanding of mechanisms underlying DA/glutamate co-release from these neurons may therefore shed new light on schizophrenia pathophysiology and lead to more effective therapeutics.
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Affiliation(s)
- Silas A Buck
- Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15213, USA
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - M Quincy Erickson-Oberg
- Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15213, USA
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Ryan W Logan
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
- Center for Systems Neuroscience, Boston University, Boston, MA, 02118, USA
| | - Zachary Freyberg
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
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Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model. Int J Mol Sci 2022; 23:ijms23169419. [PMID: 36012679 PMCID: PMC9408838 DOI: 10.3390/ijms23169419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/14/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
Symptoms of schizophrenia (SZ) typically emerge during adolescence to young adulthood, which gives a window before full-blown psychosis for early intervention. Strategies for preventing the conversion from the prodromal phase to the psychotic phase are warranted. Heterozygous (Het) Disc1 mutant mice are considered a prodromal model of SZ, suitable for studying psychotic conversion. We evaluated the preventive effect of chronic N-acetylcysteine (NAC) administration, covering the prenatal era to adulthood, on the reaction following the Amph challenge, which mimics the outbreak or conversion of psychosis, in adult Het Disc1 mice. Biochemical and morphological features were examined in the striatum of NAC-treated mice. Chronic NAC treatment normalized the Amph-induced activity in the Het Disc1 mice. Furthermore, the striatal phenotypes of Het Disc1 mice were rescued by NAC including dopamine receptors, the expression of GSK3s, MSN dendritic impairments, and striatal PV density. The current study demonstrated a potent preventive effect of chronic NAC treatment in Disc1 Het mice on the acute Amph test, which mimics the outbreak of psychosis. Our findings not only support the benefit of NAC as a dietary supplement for SZ prodromes, but also advance our knowledge of striatal dopamine receptors, PV neurons, and GSK3 signaling pathways as therapeutic targets for treating or preventing the pathogenesis of mental disorders.
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Sánchez‐Olguin CP, Zamudio SR, Guzmán‐Velázquez S, Márquez‐Portillo M, Caba‐Flores MD, Camacho‐Abrego I, Flores G, Melo AI. Neonatal ventral hippocampus lesion disrupts maternal behavior in rats: An animal model of schizophrenia. Dev Psychobiol 2022; 64:e22283. [DOI: 10.1002/dev.22283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/08/2022] [Accepted: 04/17/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Claudia P. Sánchez‐Olguin
- Departamento de Fisiología Escuela Nacional de Ciencias Biológicas Instituto Politécnico Nacional Mexico City Mexico
- Maestría en Ciencias Biológicas Universidad Autónoma de Tlaxcala Tlaxcala Mexico
| | - Sergio R. Zamudio
- Departamento de Fisiología Escuela Nacional de Ciencias Biológicas Instituto Politécnico Nacional Mexico City Mexico
| | - Sonia Guzmán‐Velázquez
- Departamento de Fisiología Escuela Nacional de Ciencias Biológicas Instituto Politécnico Nacional Mexico City Mexico
| | - Mariana Márquez‐Portillo
- Centro de Investigación en Reproducción Animal CINVESTAV Laboratorio Tlaxcala Universidad Autónoma de Tlaxcala Tlaxcala Mexico
| | | | - Israel Camacho‐Abrego
- Laboratorio de Neuropsiquiatría Instituto de Fisiología Benemérita Universidad Autónoma de Puebla Puebla Mexico
- Doctorado en Ciencias Biológicas Universidad Autónoma de Tlaxcala Tlaxcala Mexico
| | - Gonzalo Flores
- Laboratorio de Neuropsiquiatría Instituto de Fisiología Benemérita Universidad Autónoma de Puebla Puebla Mexico
| | - Angel I. Melo
- Centro de Investigación en Reproducción Animal CINVESTAV Laboratorio Tlaxcala Universidad Autónoma de Tlaxcala Tlaxcala Mexico
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Iftikhar A, Nausheen R, Muzaffar H, Naeem MA, Farooq M, Khurshid M, Almatroudi A, Alrumaihi F, Allemailem KS, Anwar H. Potential Therapeutic Benefits of Honey in Neurological Disorders: The Role of Polyphenols. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27103297. [PMID: 35630774 PMCID: PMC9143627 DOI: 10.3390/molecules27103297] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 05/16/2022] [Accepted: 05/18/2022] [Indexed: 11/26/2022]
Abstract
Honey is the principal premier product of beekeeping familiar to Homo for centuries. In every geological era and culture, evidence can be traced to the potential usefulness of honey in several ailments. With the advent of recent scientific approaches, honey has been proclaimed as a potent complementary and alternative medicine for the management and treatment of several maladies including various neurological disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, etc. In the literature archive, oxidative stress and the deprivation of antioxidants are believed to be the paramount cause of many of these neuropathies. Since different types of honey are abundant with certain antioxidants, primarily in the form of diverse polyphenols, honey is undoubtedly a strong pharmaceutic candidate against multiple neurological diseases. In this review, we have indexed and comprehended the involved mechanisms of various constituent polyphenols including different phenolic acids, flavonoids, and other phytochemicals that manifest multiple antioxidant effects in various neurological disorders. All these mechanistic interpretations of the nutritious components of honey explain and justify the potential recommendation of sweet nectar in ameliorating the burden of neurological disorders that have significantly increased across the world in the last few decades.
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Affiliation(s)
- Arslan Iftikhar
- Department of Physiology, Government College University Faisalabad, Faisalabad 38000, Pakistan; (A.I.); (R.N.); (H.M.)
| | - Rimsha Nausheen
- Department of Physiology, Government College University Faisalabad, Faisalabad 38000, Pakistan; (A.I.); (R.N.); (H.M.)
| | - Humaira Muzaffar
- Department of Physiology, Government College University Faisalabad, Faisalabad 38000, Pakistan; (A.I.); (R.N.); (H.M.)
| | - Muhammad Ahsan Naeem
- Department of Basic Sciences, KBCMA College of Veterinary and Animal Sciences, Narowal 51600, Pakistan;
| | - Muhammad Farooq
- Department of Clinical Sciences, College of Veterinary and Animal Sciences, Jhang 35200, Pakistan;
| | - Mohsin Khurshid
- Department of Microbiology, Government College University Faisalabad, Faisalabad 38000, Pakistan;
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.A.); (F.A.)
| | - Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.A.); (F.A.)
| | - Khaled S. Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.A.); (F.A.)
- Correspondence: (H.A.); (K.S.A.)
| | - Haseeb Anwar
- Department of Physiology, Government College University Faisalabad, Faisalabad 38000, Pakistan; (A.I.); (R.N.); (H.M.)
- Correspondence: (H.A.); (K.S.A.)
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Swain SA, Sarangi P, Rattan R, Sahu PK, Lamare AA. A Study of Nuclear Factor-Kappa B1 Gene Polymorphism Types in Schizophrenia Patients and Their Correlation With Disease Severity. Cureus 2022; 14:e24401. [PMID: 35619863 PMCID: PMC9125008 DOI: 10.7759/cureus.24401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2022] [Indexed: 11/05/2022] Open
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Rogóż Z, Lech MA, Chamera K, Wąsik A. The Effect of Glutathione Deficit During Early Postnatal Brain Development on the Prepulse Inhibition and Monoamine Levels in Brain Structures of Adult Sprague-Dawley Rats. Neurotox Res 2022; 40:733-750. [PMID: 35386024 DOI: 10.1007/s12640-022-00496-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/07/2022] [Accepted: 03/22/2022] [Indexed: 10/18/2022]
Abstract
Recent studies suggest that impaired glutathione synthesis and distorted dopaminergic transmission are important factors in the pathophysiology of schizophrenia. In the present study, on the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, L-buthionine-(S,R)- sulfoximine (BSO, 3.8 or 7.6 mmol/kg), and the dopamine uptake inhibitor, GBR 12,909 (5 mg/kg) alone or in combination, and prepulse inhibition of the acoustic startle response (PPI) was evaluated in adult 90-day-old rats. Moreover, the monoamine levels in the cortex and hippocampus of 16-day-old rats or 91-day-old rats were measured. The present results showed that administration of BSO at 3.8 mmol/kg led to a decreasing tendency in PPI for all tested prepulse intensities. In contrast, a combined treatment with BSO in both studied doses and GBR 12,909 did not induce significant deficits in PPI. Moreover, the results of biochemical studies indicated that treatment with BSO or GBR 12,909 alone induced a weak increase in the activity of dopaminergic, serotonergic, and noradrenergic systems in the frontal cortex and hippocampus of 16-day-old rats and 91-day-old rats. However, the combined administration of both substances allowed for maintaining the normal activity of monoaminergic systems in the rat brain. The most significant changes in the functioning of monoaminergic systems were observed in the frontal cortex of 16-day-old rats. Therefore, it seems that the frontal cortex of rat puppies is most sensitive to glutathione deficiencies resulting in increased oxidative stress in neurons. As a result, it can lead to cognitive and memory impairment.
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Affiliation(s)
- Zofia Rogóż
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland
| | - Marta A Lech
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland
| | - Katarzyna Chamera
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland
| | - Agnieszka Wąsik
- Department of Neurochemistry, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland.
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Hu L, Zhang L. Adult neural stem cells and schizophrenia. World J Stem Cells 2022; 14:219-230. [PMID: 35432739 PMCID: PMC8968214 DOI: 10.4252/wjsc.v14.i3.219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/18/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.
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Affiliation(s)
- Ling Hu
- Department of Laboratory Animal Science and Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center) and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
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Wei Q, Yan W, Zhang R, Yang X, Xie S. Aberrant cortical surface and cognition function in drug-naive first-episode schizophrenia. Ann Gen Psychiatry 2022; 21:4. [PMID: 35144626 PMCID: PMC8830089 DOI: 10.1186/s12991-022-00381-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 01/23/2022] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE Impaired cognitive function is a central symptom of schizophrenia and is often correlated with inferior global functional outcomes. However, the role of some neurobiological factors such as cortical structure alterations in the underlying cognitive damages in schizophrenia remains unclear. The present study attempted to explore the neurobiomarkers of cognitive function in drug-naive, first-episode schizophrenia by using structural magnetic resonance imaging (MRI). METHODS The present study was conducted in patients with drug-naive, first-episode schizophrenia (SZ) and healthy controls (HCs). MRI T1 images were pre-processed using CAT12. Surface-based morphometry (SBM) was utilised to evaluate structural parameters such as cortical thickness and sulcus depth. The positive and negative syndrome scale (PANSS) and Chinese version of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus cognitive battery (MCCB) were employed to estimate the psychotic symptoms and cognition, respectively. RESULTS A total of 117 patients with drug-naive first-episode schizophrenia (SZ) and 98 healthy controls (HCs) were included. Both the cortical thickness and sulcus depth in the frontal lobe were lower in patients with SZ than in the HCs under family-wise error correction (p < 0.05). Attention and visual learning in MCCB were positively correlated with the right lateral orbitofrontal cortical thickness in the patients with SZ (p < 0.01). CONCLUSIONS The reduced surface value of multiple cortical structures, particularly the cortical thickness and sulcus depth in the frontal lobe, could be the potential biomarkers for cognitive impairment in SZ.
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Affiliation(s)
- Qianqian Wei
- Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Wei Yan
- Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Rongrong Zhang
- Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Xuna Yang
- Medical Department, Suzhou Guangji Hospital, Suzhou, 215008, China.
| | - Shiping Xie
- Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China.
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Beeraka NM, Avila-Rodriguez MF, Aliev G. Recent Reports on Redox Stress-Induced Mitochondrial DNA Variations, Neuroglial Interactions, and NMDA Receptor System in Pathophysiology of Schizophrenia. Mol Neurobiol 2022; 59:2472-2496. [PMID: 35083660 DOI: 10.1007/s12035-021-02703-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/14/2021] [Indexed: 10/19/2022]
Abstract
Schizophrenia (SZ) is a chronic psychiatric disorder affecting several people worldwide. Mitochondrial DNA (mtDNA) variations could invoke changes in the OXPHOS system, calcium buffering, and ROS production, which have significant implications for glial cell survival during SZ. Oxidative stress has been implicated in glial cells-mediated pathogenesis of SZ; the brain comparatively more prone to oxidative damage through NMDAR. A confluence of scientific evidence points to mtDNA alterations, Nrf2 signaling, dynamic alterations in dorsolateral prefrontal cortex (DLPFC), and provocation of oxidative stress that enhance pathophysiology of SZ. Furthermore, the alterations in excitatory signaling related to NMDAR signaling were particularly reported for SZ pathophysiology. Current review reported the recent evidence for the role of mtDNA variations and oxidative stress in relation to pathophysiology of SZ, NMDAR hypofunction, and glutathione deficiency. NMDAR system is influenced by redox dysregulation in oxidative stress, inflammation, and antioxidant mediators. Several studies have demonstrated the relationship of these variables on severity of pathophysiology in SZ. An extensive literature search was conducted using Medline, PubMed, PsycINFO, CINAHL PLUS, BIOSIS Preview, Google scholar, and Cochrane databases. We summarize consistent evidence pointing out a plausible model that may elucidate the crosstalk between mtDNA alterations in glial cells and redox dysregulation during oxidative stress and the perturbation of NMDA neurotransmitter system during current therapeutic modalities for the SZ treatment. This review can be beneficial for the development of promising novel diagnostics, and therapeutic modalities by ascertaining the mtDNA variations, redox state, and efficacy of pharmacological agents to mitigate redox dysregulation and augment NMDAR function to treat cognitive and behavioral symptoms in SZ.
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Affiliation(s)
- Narasimha M Beeraka
- Department of Human Anatomy, I M Sechenov First Moscow State Medical University (Sechenov University), St. Trubetskaya, 8, bld. 2, Moscow, 119991, Russia.
| | - Marco F Avila-Rodriguez
- Faculty of Health Sciences, Department of Clinical Sciences, Barrio Santa Helena, University of Tolima, 730006, Ibagué, Colombia
| | - Gjumrakch Aliev
- Department of Human Anatomy, I M Sechenov First Moscow State Medical University (Sechenov University), St. Trubetskaya, 8, bld. 2, Moscow, 119991, Russia.,Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, 142432, Russia.,Research Institute of Human Morphology, 3 Tsyurupy Street, Moscow, 117418, Russia.,GALLY International Research Institute, 7733 Louis Pasteur Drive, #330, San Antonio, TX, 78229, USA
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Durnaoglu S, Lee SK, Ahnn J. Syncytin, envelope protein of human endogenous retrovirus (HERV): no longer 'fossil' in human genome. Anim Cells Syst (Seoul) 2022; 25:358-368. [PMID: 35059135 PMCID: PMC8765258 DOI: 10.1080/19768354.2021.2019109] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 12/07/2021] [Indexed: 12/17/2022] Open
Abstract
Human endogenous retroviruses (HERVs) are 'fossil viruses' that resulted from stable integrations of exogenous retroviruses throughout evolution. HERVs are defective and do not produce infectious viral particles. However, some HERVs retain a limited coding capacity and produce retroviral transcripts and proteins, which function in human developmental process and various pathologies, including many cancers and neurological diseases. Recently, it has been reported that HERVs are differently expressed in COVID-19 disease caused by infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we discuss the molecular structure and function of HERV ENV proteins, particularly syncytins, and their conventional roles in human development and diseases, and potential involvement in COVID-19 regarding the newly reported mental symptoms. We also address COVID-19 vaccine-related infertility concerns arising from the similarity of syncytin with the spike protein of SARS-CoV-2, which have been proved invalid.
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Affiliation(s)
- Serpen Durnaoglu
- College of Natural Sciences, Hanyang University, Seoul, Republic of Korea
- Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea
| | - Sun-Kyung Lee
- College of Natural Sciences, Hanyang University, Seoul, Republic of Korea
- Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea
| | - Joohong Ahnn
- College of Natural Sciences, Hanyang University, Seoul, Republic of Korea
- Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea
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Cherubini E, Di Cristo G, Avoli M. Dysregulation of GABAergic Signaling in Neurodevelomental Disorders: Targeting Cation-Chloride Co-transporters to Re-establish a Proper E/I Balance. Front Cell Neurosci 2022; 15:813441. [PMID: 35069119 PMCID: PMC8766311 DOI: 10.3389/fncel.2021.813441] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 11/30/2021] [Indexed: 01/01/2023] Open
Abstract
The construction of the brain relies on a series of well-defined genetically and experience- or activity -dependent mechanisms which allow to adapt to the external environment. Disruption of these processes leads to neurological and psychiatric disorders, which in many cases are manifest already early in postnatal life. GABA, the main inhibitory neurotransmitter in the adult brain is one of the major players in the early assembly and formation of neuronal circuits. In the prenatal and immediate postnatal period GABA, acting on GABAA receptors, depolarizes and excites targeted cells via an outwardly directed flux of chloride. In this way it activates NMDA receptors and voltage-dependent calcium channels contributing, through intracellular calcium rise, to shape neuronal activity and to establish, through the formation of new synapses and elimination of others, adult neuronal circuits. The direction of GABAA-mediated neurotransmission (depolarizing or hyperpolarizing) depends on the intracellular levels of chloride [Cl−]i, which in turn are maintained by the activity of the cation-chloride importer and exporter KCC2 and NKCC1, respectively. Thus, the premature hyperpolarizing action of GABA or its persistent depolarizing effect beyond the postnatal period, leads to behavioral deficits associated with morphological alterations and an excitatory (E)/inhibitory (I) imbalance in selective brain areas. The aim of this review is to summarize recent data concerning the functional role of GABAergic transmission in building up and refining neuronal circuits early in development and its dysfunction in neurodevelopmental disorders such as Autism Spectrum Disorders (ASDs), schizophrenia and epilepsy. In particular, we focus on novel information concerning the mechanisms by which alterations in cation-chloride co-transporters (CCC) generate behavioral and cognitive impairment in these diseases. We discuss also the possibility to re-establish a proper GABAA-mediated neurotransmission and excitatory (E)/inhibitory (I) balance within selective brain areas acting on CCC.
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Affiliation(s)
- Enrico Cherubini
- European Brain Research Institute (EBRI)-Rita Levi-Montalcini, Roma, Italy
- *Correspondence: Enrico Cherubini
| | - Graziella Di Cristo
- Neurosciences Department, Université de Montréal and CHU Sainte-Justine Research Center, Montreal, QC, Canada
| | - Massimo Avoli
- Montreal Neurological Institute-Hospital and Departments of Neurology and Neurosurgery and of Physiology, McGill University, Montreal, QC, Canada
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Lin C, Hu Q, Dong J, Wei Z, Li J, Chen Z. Serum metabolic signatures of schizophrenia patients complicated with hepatitis B virus infection: A 1H NMR-based metabolomics study. Front Psychiatry 2022; 13:998709. [PMID: 36620683 PMCID: PMC9810819 DOI: 10.3389/fpsyt.2022.998709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Schizophrenia (SZ) is a severe chronic mental disorder with increased risk of hepatitis B virus (HBV) infection, which is incurable currently and induces various negative emotions and psychological pressures in patients to exacerbate mental disorders. To facilitate the therapeutic design for SZ patients complicated with HBV infection (SZ + HBV), it is helpful to first elucidate the metabolic perturbations in SZ + HBV patients. METHODS In this study, metabolic profiles of the serum samples from four groups of participants comprising healthy controls (HC, n = 72), HBV infection (n = 52), SZ patients (n = 37), and SZ + HBV (n = 41) patients were investigated using a high-resolution 1H NMR-based metabolomics approach. RESULTS AND DISCUSSION Distinguishable metabolic profiles were found in the four groups. In comparison with HC, HBV infection induced increased levels of citrate and succinate to perturbate the tricarboxylic acid cycle and succinate-related pathways. Similar to SZ cases, SZ + HBV patients exhibited decreased glucose but increased citrate, pyruvate, and lactate, suggesting the occurrence of disturbance in glucose metabolism. Moreover, in comparison with HC, several serum amino acid levels in SZ + HBV patients were significantly altered. Our findings suggest that Warburg effect, energy metabolism disorders, neurotransmitter metabolism abnormalities, mitochondrial dysfunction and several disturbed pathways in relation to tyrosine and choline appear to play specific and central roles in the pathophysiology of SZ + HBV. Apart from replicating metabolic alterations induced by SZ and HBV separately (e.g., in energy metabolism and Warburg effect), the specific metabolic abnormalities in the SZ + HBV group (e.g., several tyrosine- and choline-related pathways) highlighted the existence of a synergistic action between SZ and HBV pathologies. Current study revealed the metabolic alterations specific to the interaction between SZ and HBV pathologies, and may open important perspectives for designing precise therapies for SZ + HBV patients beyond the simple combination of two individual treatments.
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Affiliation(s)
- Caigui Lin
- Fujian Provincial Key Laboratory for Plasma and Magnetic Resonance, Department of Electronic Science, Xiamen University, Xiamen, Fujian, China.,National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian, China
| | - Qing Hu
- Xiamen Xianyue Hospital, Xiamen, Fujian, China
| | - Jiyang Dong
- Fujian Provincial Key Laboratory for Plasma and Magnetic Resonance, Department of Electronic Science, Xiamen University, Xiamen, Fujian, China
| | - Zhiliang Wei
- Department of Radiology, Johns Hopkins University, Baltimore, MD, United States
| | - Jie Li
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China
| | - Zhong Chen
- Fujian Provincial Key Laboratory for Plasma and Magnetic Resonance, Department of Electronic Science, Xiamen University, Xiamen, Fujian, China
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Carroll MJ, Garcia-Reyero N, Perkins EJ, Lauffenburger DA. Translatable pathways classification (TransPath-C) for inferring processes germane to human biology from animal studies data: example application in neurobiology. Integr Biol (Camb) 2021; 13:237-245. [PMID: 34849940 DOI: 10.1093/intbio/zyab016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 11/13/2022]
Abstract
How to translate insights gained from studies in one organismal species for what is most likely to be germane in another species, such as from mice to humans, is a ubiquitous challenge in basic biology as well as biomedicine. This is an especially difficult problem when there are few molecular features that are obviously important in both species for a given phenotype of interest. Neuropathologies are a prominent realm of this complication. Schizophrenia is complex psychiatric disorder that affects 1% of the population. Many genetic factors have been proposed to drive the development of schizophrenia, and the 22q11 microdeletion (MD) syndrome has been shown to dramatically increase this risk. Due to heterogeneity of presentation of symptoms, diagnosis and formulation of treatment options for patients can often be delayed, and there is an urgent need for novel therapeutics directed toward the treatment of schizophrenia. Here, we present a novel computational approach, Translational Pathways Classification (TransPath-C), that can be used to identify shared pathway dysregulation between mouse models and human schizophrenia cohorts. This method uses variation of pathway activation in the mouse model to predict both mouse and human disease phenotype. Analysis of shared dysregulated pathways called out by both the mouse and human classifiers of TransPath-C can identify pathways that can be targeted in both preclinical and human cohorts of schizophrenia. In application to the 22q11 MD mouse model, our findings suggest that PAR1 pathway activation found upregulated in this mouse phenotype is germane for the corresponding human schizophrenia cohort such that inhibition of PAR1 may offer a novel therapeutic target.
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Affiliation(s)
- Molly J Carroll
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Natàlia Garcia-Reyero
- Environmental Laboratory, US Army Engineer Research & Development Center, Vicksburg, MS, USA
| | - Edward J Perkins
- Environmental Laboratory, US Army Engineer Research & Development Center, Vicksburg, MS, USA
| | - Douglas A Lauffenburger
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
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Jiang Y, Patton MH, Zakharenko SS. A Case for Thalamic Mechanisms of Schizophrenia: Perspective From Modeling 22q11.2 Deletion Syndrome. Front Neural Circuits 2021; 15:769969. [PMID: 34955759 PMCID: PMC8693383 DOI: 10.3389/fncir.2021.769969] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Schizophrenia is a severe, chronic psychiatric disorder that devastates the lives of millions of people worldwide. The disease is characterized by a constellation of symptoms, ranging from cognitive deficits, to social withdrawal, to hallucinations. Despite decades of research, our understanding of the neurobiology of the disease, specifically the neural circuits underlying schizophrenia symptoms, is still in the early stages. Consequently, the development of therapies continues to be stagnant, and overall prognosis is poor. The main obstacle to improving the treatment of schizophrenia is its multicausal, polygenic etiology, which is difficult to model. Clinical observations and the emergence of preclinical models of rare but well-defined genomic lesions that confer substantial risk of schizophrenia (e.g., 22q11.2 microdeletion) have highlighted the role of the thalamus in the disease. Here we review the literature on the molecular, cellular, and circuitry findings in schizophrenia and discuss the leading theories in the field, which point to abnormalities within the thalamus as potential pathogenic mechanisms of schizophrenia. We posit that synaptic dysfunction and oscillatory abnormalities in neural circuits involving projections from and within the thalamus, with a focus on the thalamocortical circuits, may underlie the psychotic (and possibly other) symptoms of schizophrenia.
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Affiliation(s)
| | | | - Stanislav S. Zakharenko
- Division of Neural Circuits and Behavior, Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, United States
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Benchoua A, Lasbareilles M, Tournois J. Contribution of Human Pluripotent Stem Cell-Based Models to Drug Discovery for Neurological Disorders. Cells 2021; 10:cells10123290. [PMID: 34943799 PMCID: PMC8699352 DOI: 10.3390/cells10123290] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023] Open
Abstract
One of the major obstacles to the identification of therapeutic interventions for central nervous system disorders has been the difficulty in studying the step-by-step progression of diseases in neuronal networks that are amenable to drug screening. Recent advances in the field of human pluripotent stem cell (PSC) biology offers the capability to create patient-specific human neurons with defined clinical profiles using reprogramming technology, which provides unprecedented opportunities for both the investigation of pathogenic mechanisms of brain disorders and the discovery of novel therapeutic strategies via drug screening. Many examples not only of the creation of human pluripotent stem cells as models of monogenic neurological disorders, but also of more challenging cases of complex multifactorial disorders now exist. Here, we review the state-of-the art brain cell types obtainable from PSCs and amenable to compound-screening formats. We then provide examples illustrating how these models contribute to the definition of new molecular or functional targets for drug discovery and to the design of novel pharmacological approaches for rare genetic disorders, as well as frequent neurodegenerative diseases and psychiatric disorders.
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Affiliation(s)
- Alexandra Benchoua
- Neuroplasticity and Therapeutics, CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France;
- High Throughput Screening Platform, CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France;
- Correspondence:
| | - Marie Lasbareilles
- Neuroplasticity and Therapeutics, CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France;
- UEVE UMR 861, I-STEM, AFM, 91100 Corbeil-Essonnes, France
| | - Johana Tournois
- High Throughput Screening Platform, CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France;
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Wang Y, Wang X, Harlin M, Larsen F, Panni M, Yildirim M, Madera J, Arias L, Forbes A, Mustafa N, Ruiz-White I, Raoufinia A. An alternative start regimen with aripiprazole once-monthly in patients with schizophrenia: population pharmacokinetic analysis of a single-day, two-injection start with gluteal and/or deltoid intramuscular injection. Curr Med Res Opin 2021; 37:1961-1972. [PMID: 34407720 DOI: 10.1080/03007995.2021.1965974] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND The single-injection start regimen for aripiprazole once-monthly 400 mg (AOM 400) in patients with schizophrenia requires a single intramuscular injection in the gluteal or deltoid site and 14 days of concurrent oral therapy. A simplified, single-day regimen of two injections at separate gluteal and/or deltoid injection sites, together with a single 20-mg dose of oral aripiprazole on the 1st day, was assessed. PATIENTS AND METHODS A previously developed population-pharmacokinetic (popPK) model for characterizing aripiprazole PK following oral administration and gluteal intramuscular depot injection was expanded to include deltoid injection. Simulations were conducted to assess PK profiles following various (including two-injection) start regimens. Postmarketing data on patients who received higher-than-recommended AOM doses were used to assess overall safety/tolerability. RESULTS The two-injection start regimen with a single concurrent oral dose displayed a comparable PK profile to the single-injection start regimen with concurrent 14-day oral administration in simulations. The safety assessment indicated the two-injection start regimen was unlikely to be associated with safety concerns beyond those expected with a single-injection start regimen. CONCLUSION These data support use of the two-injection start regimen in clinical practice to reduce reliance on daily oral administration and optimize the therapeutic benefits of AOM 400 in patients with schizophrenia.
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Affiliation(s)
- Yanlin Wang
- Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA
| | - Xiaofeng Wang
- Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA
| | - Matt Harlin
- Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA
| | | | - Moeen Panni
- Otsuka Pharmaceutical Europe Ltd, Wexham, UK
| | | | - Jessica Madera
- Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA
| | | | - Andy Forbes
- Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA
| | - Nihal Mustafa
- Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA
| | - Inez Ruiz-White
- Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA
| | - Arash Raoufinia
- Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA
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Kruk-Slomka M, Biala G. Cannabidiol Attenuates MK-801-Induced Cognitive Symptoms of Schizophrenia in the Passive Avoidance Test in Mice. Molecules 2021; 26:molecules26195977. [PMID: 34641522 PMCID: PMC8513030 DOI: 10.3390/molecules26195977] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 11/16/2022] Open
Abstract
Schizophrenia is a chronic mental disorder that disturbs feelings and behavior. The symptoms of schizophrenia fall into three categories: positive, negative, and cognitive. Cognitive symptoms are characterized by memory loss or attentional deficits, and are especially difficult to treat. Thus, there is intense research into the development of new treatments for schizophrenia-related responses. One of the possible strategies is connected with cannabidiol (CBD), a cannabinoid compound. This research focuses on the role of CBD in different stages of memory (acquisition, consolidation, retrieval) connected with fear conditioning in the passive avoidance (PA) learning task in mice, as well as in the memory impairment typical of cognitive symptoms of schizophrenia. Memory impairment was provoked by an acute injection of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (animal model of schizophrenia). Our results revealed that an acute injection of CBD (30 mg/kg; intraperitoneally (i.p.) improved all phases of long-term fear memory in the PA test in mice. Moreover, the acute injection of non-effective doses of CBD (1 or 5 mg/kg; i.p.) attenuated the memory impairment provoked by MK-801 (0.6 mg/kg; i.p.) in the consolidation and retrieval stages of fear memory, but not in the acquisition of memory. The present findings confirm that CBD has a positive influence on memory and learning processes in mice, and reveals that this cannabinoid compound is able to attenuate memory impairment connected with hypofunction of glutamate transmission in a murine model of schizophrenia.
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Khanal P, Hotulainen P. Dendritic Spine Initiation in Brain Development, Learning and Diseases and Impact of BAR-Domain Proteins. Cells 2021; 10:cells10092392. [PMID: 34572042 PMCID: PMC8468246 DOI: 10.3390/cells10092392] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 02/08/2023] Open
Abstract
Dendritic spines are small, bulbous protrusions along neuronal dendrites where most of the excitatory synapses are located. Dendritic spine density in normal human brain increases rapidly before and after birth achieving the highest density around 2-8 years. Density decreases during adolescence, reaching a stable level in adulthood. The changes in dendritic spines are considered structural correlates for synaptic plasticity as well as the basis of experience-dependent remodeling of neuronal circuits. Alterations in spine density correspond to aberrant brain function observed in various neurodevelopmental and neuropsychiatric disorders. Dendritic spine initiation affects spine density. In this review, we discuss the importance of spine initiation in brain development, learning, and potential complications resulting from altered spine initiation in neurological diseases. Current literature shows that two Bin Amphiphysin Rvs (BAR) domain-containing proteins, MIM/Mtss1 and SrGAP3, are involved in spine initiation. We review existing literature and open databases to discuss whether other BAR-domain proteins could also take part in spine initiation. Finally, we discuss the potential molecular mechanisms on how BAR-domain proteins could regulate spine initiation.
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Affiliation(s)
- Pushpa Khanal
- Minerva Foundation Institute for Medical Research, Tukholmankatu 8, 00290 Helsinki, Finland;
- HiLIFE-Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland
| | - Pirta Hotulainen
- Minerva Foundation Institute for Medical Research, Tukholmankatu 8, 00290 Helsinki, Finland;
- Correspondence:
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Vafadari B. Stress and the Role of the Gut-Brain Axis in the Pathogenesis of Schizophrenia: A Literature Review. Int J Mol Sci 2021; 22:ijms22189747. [PMID: 34575911 PMCID: PMC8471971 DOI: 10.3390/ijms22189747] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/19/2021] [Accepted: 08/31/2021] [Indexed: 12/21/2022] Open
Abstract
Schizophrenia is a severe neuropsychiatric disorder, and its etiology remains largely unknown. Environmental factors have been reported to play roles in the pathogenesis of schizophrenia, and one of the major environmental factors identified for this disorder is psychosocial stress. Several studies have suggested that stressful life events, as well as the chronic social stress associated with city life, may lead to the development of schizophrenia. The other factor is the gut–brain axis. The composition of the gut microbiome and alterations thereof may affect the brain and may lead to schizophrenia. The main interest of this review article is in overviewing the major recent findings on the effects of stress and the gut–brain axis, as well as their possible bidirectional effects, in the pathogenesis of schizophrenia.
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Affiliation(s)
- Behnam Vafadari
- Clinic for Anesthesiology, University Medical Center Göttingen, Georg-August-University, 37073 Göttingen, Germany
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Cystine/Glutamate Antiporter in Schizophrenia: From Molecular Mechanism to Novel Biomarker and Treatment. Int J Mol Sci 2021; 22:ijms22189718. [PMID: 34575878 PMCID: PMC8466274 DOI: 10.3390/ijms22189718] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/06/2021] [Accepted: 09/06/2021] [Indexed: 01/04/2023] Open
Abstract
Glutamate, a crucial excitatory neurotransmitter, plays a major role in the modulation of schizophrenia’s pathogenesis. New drug developments for schizophrenia have been prompted by the hypoglutamatergic hypothesis of schizophrenia. The cystine/glutamate antiporter system xc− is related to glutamate-release regulation. Patients with schizophrenia were recently discovered to exhibit downregulation of xc− subunits—the solute carrier (SLC) family 3 member 2 and the SLC family 7 member 11. We searched for relevant studies from 1980, when Bannai and Kitamura first identified the protein subunit system xc− in lung fibroblasts, with the aim of compiling the biological, functional, and pharmacological characteristics of antiporter xc−, which consists of several subunits. Some of them can significantly stimulate the human brain through the glutamate pathway. Initially, extracellular cysteine activates neuronal xc−, causing glutamate efflux. Next, excitatory amino acid transporters enhance the unidirectional transportation of glutamate and sodium. These two biochemical pathways are also crucial to the production of glutathione, a protective agent for neural and glial cells and astrocytes. Investigation of the expression of system xc− genes in the peripheral white blood cells of patients with schizophrenia can facilitate better understanding of the mental disorder and future development of novel biomarkers and treatments for schizophrenia. In addition, the findings further support the hypoglutamatergic hypothesis of schizophrenia.
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Grubisha MJ, Sun X, MacDonald ML, Garver M, Sun Z, Paris KA, Patel DS, DeGiosio RA, Lewis DA, Yates NA, Camacho C, Homanics GE, Ding Y, Sweet RA. MAP2 is differentially phosphorylated in schizophrenia, altering its function. Mol Psychiatry 2021; 26:5371-5388. [PMID: 33526823 PMCID: PMC8325721 DOI: 10.1038/s41380-021-01034-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 01/04/2021] [Accepted: 01/15/2021] [Indexed: 01/30/2023]
Abstract
Schizophrenia (Sz) is a highly polygenic disorder, with common, rare, and structural variants each contributing only a small fraction of overall disease risk. Thus, there is a need to identify downstream points of convergence that can be targeted with therapeutics. Reduction of microtubule-associated protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in individuals with Sz, despite no change in MAP2 protein levels. MAP2 is phosphorylated downstream of multiple receptors and kinases identified as Sz risk genes, altering its immunoreactivity and function. Using an unbiased phosphoproteomics approach, we quantified 18 MAP2 phosphopeptides, 9 of which were significantly altered in Sz subjects. Network analysis grouped MAP2 phosphopeptides into three modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in Sz subjects. We then investigated the most hyperphosphorylated site in Sz, phosphoserine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. We generated a transgenic mouse containing a phosphomimetic mutation at S1782 (S1782E) and found reductions in basilar dendritic length and complexity along with reduced spine density. Because only a limited number of MAP2 interacting proteins have been previously identified, we combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in mouse brain. The MAP2 interactome was enriched for proteins involved in protein translation. These associations were shown to be functional as overexpression of wild type and phosphomimetic MAP2 reduced protein synthesis in vitro. Finally, we found that Sz subjects with low MAP2-IR had reductions in the levels of synaptic proteins relative to nonpsychiatric control (NPC) subjects and to Sz subjects with normal and MAP2-IR, and this same pattern was recapitulated in S1782E mice. These findings suggest a new conceptual framework for Sz-that a large proportion of individuals have a "MAP2opathy"-in which MAP function is altered by phosphorylation, leading to impairments of neuronal structure, synaptic protein synthesis, and function.
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Affiliation(s)
- M J Grubisha
- Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - X Sun
- Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Tsinghua MD Program, School of Medicine, Tsinghua University, Beijing, China
| | - M L MacDonald
- Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - M Garver
- Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Z Sun
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - K A Paris
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - D S Patel
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - R A DeGiosio
- Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - D A Lewis
- Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - N A Yates
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA
- Biomedical Mass Spectrometry Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - C Camacho
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - G E Homanics
- Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Y Ding
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - R A Sweet
- Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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Meditation-Induced Psychosis: Trigger and Recurrence. Case Rep Psychiatry 2021; 2021:6615451. [PMID: 34426774 PMCID: PMC8380174 DOI: 10.1155/2021/6615451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 06/24/2021] [Accepted: 08/08/2021] [Indexed: 11/22/2022] Open
Abstract
Meditation is regarded as a self-regulation approach to manage emotions. Meditation has a beneficial effect on mental health. Different kinds of meditation are practiced in many religions and cultures for the general wellbeing of an individual. However, meditation-related experiences and negative effects of meditation are not uncommon. Meditation-induced psychosis has been reported in the past. Here, we present a case of a 33-year-old male patient who developed acute and transient psychosis twice after meditation and discuss the role of meditation as a precipitating factor to psychosis.
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Lech MA, Kamińska K, Leśkiewicz M, Lorenc-Koci E, Rogóż Z. Impact of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behaviors and BDNF mRNA expression in the adult Sprague-Dawley rats exposed to glutathione deficit during early postnatal development of the brain. Pharmacol Rep 2021; 73:1712-1723. [PMID: 34398437 PMCID: PMC8599398 DOI: 10.1007/s43440-021-00318-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 10/27/2022]
Abstract
BACKGROUND Preclinical and clinical studies have indicated that impaired endogenous synthesis of glutathione during early postnatal development plays a significant role in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and cognitive symptoms of schizophrenia. METHODS In the present study, we investigated the influence of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behavior and BDNF mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Male pups between the postnatal days p5-p16 were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12,909 alone or in combination. Escitalopram and aripiprazole were given repeatedly for 21 days before the tests. On p90-92 rats were evaluated in the behavioral and biochemical tests. RESULTS BSO given alone and together with GBR 12,909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with aripiprazole and an ineffective dose of escitalopram also abolished the behavioral deficits in the studied tests. CONCLUSION The obtained data indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioral deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with aripiprazole and ineffective dose of escitalopram.
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Affiliation(s)
- Marta A Lech
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland
| | - Kinga Kamińska
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland
| | - Monika Leśkiewicz
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences,, 12 Smętna Street, Kraków, Poland
| | - Elżbieta Lorenc-Koci
- Department of Neuropsychopharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland
| | - Zofia Rogóż
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, Kraków, Poland. .,The Podhale State Higher Vocational School, Faculty of Cosmetology, Institute of Health, 71 Kokoszków, Nowy Targ, Poland.
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