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Lee D, Baek JH, Kim Y, Lee BD, Cho EY, Joo EJ, Ahn YM, Kim SH, Chung YC, Rami FZ, Kim SJ, Kim SW, Myung W, Ha TH, Lee HJ, Oh H, Lee KY, Kim MJ, Kang CY, Jeon S, Jo A, Yu H, Jeong S, Ha K, Kim B, Shim I, Cho C, Huang H, Won HH, Hong KS. Genome-wide association study and polygenic risk score analysis for schizophrenia in a Korean population. Asian J Psychiatr 2024; 102:104203. [PMID: 39293130 DOI: 10.1016/j.ajp.2024.104203] [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: 04/17/2024] [Revised: 08/13/2024] [Accepted: 08/28/2024] [Indexed: 09/20/2024]
Abstract
Although large-scale genome-wide association studies (GWASs) have revealed the genetic architecture of schizophrenia, these studies have mainly focused on populations of European ancestry. This study aimed to identify common genetic variants associated with schizophrenia in the Korean population and evaluate the performance of polygenic risk scores (PRSs) derived from large-scale GWASs across ancestries. In the Korean psychiatric GWAS project (KPGP), seven academic institutes and their affiliated hospitals across South Korea recruited a cohort of 1670 patients with DSM-IV-defined schizophrenia and 2271 healthy controls. A total of 6690,822 SNPs were tested for association with schizophrenia. We identified one previously unreported genome-wide significant locus rs2423464 (P = 2.83 × 10-11; odds ratio = 1.65; 95 % confidence interval = 1.43-1.91, minor allele frequency = 0.126). This variant was also associated with increased lysosomal-associated membrane protein family member 5 (LAMP5) gene expression. The PRS derived from the meta-analysis results of East Asian and European GWASs explained a larger proportion of the phenotypic variance in the Korean schizophrenia sample than the PRS of an East Asian or European GWAS. (R2 = 0.073 for meta-analysis; 0.028 for East Asian GWAS; 0.037 for European GWAS). GWASs involving diverse ethnic groups will expand our understanding of the genetic architecture of schizophrenia.
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Affiliation(s)
- Dongbin Lee
- Department of Digital Health, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea
| | - Ji Hyun Baek
- Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yujin Kim
- Department of Digital Health, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea
| | - Byung Dae Lee
- Pusan National University Research Park, Busan, South Korea
| | - Eun-Young Cho
- Samsung Biomedical Research Institute, Seoul, South Korea
| | - Eun-Jeong Joo
- Department of Psychiatry, Euijeongbu Eulji University Hospital, Euijeongbu, South Korea; Department of Neuropsychiatry, Eulji University, School of Medicine, Daejeon, South Korea
| | - Yong Min Ahn
- Department of Psychiatry, Seoul National University, College of Medicine, Seoul, South Korea; Department of Neuropsychiatry, Seoul National University Hospital, Seoul, South Korea
| | - Se Hyun Kim
- Department of Psychiatry, Seoul National University, College of Medicine, Seoul, South Korea; Department of Neuropsychiatry, Seoul National University Hospital, Seoul, South Korea
| | - Young-Chul Chung
- Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, South Korea; Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, South Korea
| | - Fatima Zahra Rami
- Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, South Korea; Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, South Korea
| | - Se Joo Kim
- Department of Psychiatry and Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Sung-Wan Kim
- Department of Psychiatry, Chonnam National University Medical School, Gwangju, South Korea
| | - Woojae Myung
- Department of Psychiatry, Seoul National University, College of Medicine, Seoul, South Korea; Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Tae Hyon Ha
- Department of Psychiatry, Seoul National University, College of Medicine, Seoul, South Korea; Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Heon-Jeong Lee
- Department of Psychiatry, Korea University College of Medicine, Seoul, South Korea
| | - Hayoung Oh
- Pusan National University Research Park, Pusan, South Korea
| | - Kyu Young Lee
- Department of Neuropsychiatry, Eulji University, School of Medicine, Daejeon, South Korea; Department of Psychiatry, Nowon Eulji University Hospital, Seoul, South Korea
| | - Min Ji Kim
- Department of Psychiatry, Seoul National University, College of Medicine, Seoul, South Korea; Department of Neuropsychiatry, Seoul National University Hospital, Seoul, South Korea
| | - Chae Yeong Kang
- Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, South Korea; Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, South Korea
| | - Sumoa Jeon
- Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Anna Jo
- Department of Psychiatry, Chonnam National University Medical School, Gwangju, South Korea
| | - Hyeona Yu
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Seunghwa Jeong
- Department of Psychiatry, Korea University College of Medicine, Seoul, South Korea
| | - Kyooseob Ha
- Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada; Department of Psychiatry, Lions Gate Hospital - Vancouver Coastal Health Authority, British Columbia, Canada
| | - Beomsu Kim
- Department of Precision Medicine, Sungkyunkwan University, School of Medicine, Seoul, South Korea
| | - Injeong Shim
- Department of Digital Health, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea
| | - Chamlee Cho
- Department of Digital Health, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea
| | - Hailiang Huang
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
| | - Hong-Hee Won
- Department of Digital Health, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea.
| | - Kyung Sue Hong
- Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada; Department of Psychiatry, Lions Gate Hospital - Vancouver Coastal Health Authority, British Columbia, Canada.
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Mensi MM, Guerini FR, Marchesi M, Chiappedi M, Bolognesi E, Borgatti R. SNAP-25 Polymorphisms in Autism Spectrum Disorder: A Pilot Study towards a Possible Endophenotype. Pediatr Rep 2023; 15:766-773. [PMID: 38133436 PMCID: PMC10747488 DOI: 10.3390/pediatric15040068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/23/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023] Open
Abstract
While there is substantial agreement on the diagnostic criteria for autism spectrum disorder, it is also acknowledged that it has a broad range of clinical presentations. This can complicate the diagnostic process and aggravate the choice of the most suitable rehabilitative strategy for each child. Attentional difficulties are among the most frequently reported comorbidities in autism spectrum disorder. We investigated the role of SNAP-25 polymorphisms. Synaptosome-associated protein 25 (SNAP25) is a presynaptic membrane-binding protein; it plays a crucial role in neurotransmission and has already been studied in numerous psychiatric disorders. It was also seen to be associated with hyperactivity in children with autism spectrum disorder. We collected clinical, behavioral and neuropsychological data on 41 children with a diagnosis of autism spectrum disorder, and then genotyped them for five single-nucleotide polymorphisms of SNAP-25. Participants were divided into two groups according to the Autism Diagnostic Observation Schedule (ADOS-2) Severity Score. In the group with the highest severity score, we found significant associations of clinical data with polymorphism rs363050 (A/G): children with the GG genotype had lower total IQ, more severe autistic functioning and more attentional difficulties. Our research could be the starting point for outlining a possible endophenotype among patients with autism spectrum disorder who are clinically characterized by severe autistic functioning and significant attentional difficulties.
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Affiliation(s)
- Martina Maria Mensi
- Child Neuropsychiatry Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy; (M.M.M.); (R.B.)
| | - Franca Rosa Guerini
- IRCCS Don Carlo Gnocchi Foundation—ONLUS, 20148 Milan, Italy; (F.R.G.); (E.B.)
| | - Michele Marchesi
- Child Neurology and Psychiatry Unit, ASST Pavia, 27029 Vigevano, Italy;
| | - Matteo Chiappedi
- Department of Brain and Behavioural Sciences, University of Pavia, 27100 Pavia, Italy
| | | | - Renato Borgatti
- Child Neuropsychiatry Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy; (M.M.M.); (R.B.)
- Child Neurology and Psychiatry Unit, ASST Pavia, 27029 Vigevano, Italy;
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3
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Weiss F, Caruso V, De Rosa U, Beatino MF, Barbuti M, Nicoletti F, Perugi G. The role of NMDA receptors in bipolar disorder: A systematic review. Bipolar Disord 2023; 25:624-636. [PMID: 37208966 DOI: 10.1111/bdi.13335] [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] [Indexed: 05/21/2023]
Abstract
OBJECTIVES Glutamatergic transmission and N-methyl-D-aspartate receptors (NMDARs) have been implicated in the pathophysiology schizophrenic spectrum and major depressive disorders. Less is known about the role of NMDARs in bipolar disorder (BD). The present systematic review aimed to investigate the role of NMDARs in BD, along with its possible neurobiological and clinical implications. METHODS We performed a computerized literature research on PubMed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, using the following string: (("Bipolar Disorder"[Mesh]) OR (manic-depressive disorder[Mesh]) OR ("BD") OR ("MDD")) AND ((NMDA [Mesh]) OR (N-methyl-D-aspartate) OR (NMDAR[Mesh]) OR (N-methyl-D-aspartate receptor)). RESULTS Genetic studies yield conflicting results, and the most studied candidate for an association with BD is the GRIN2B gene. Postmortem expression studies (in situ hybridization and autoradiographic and immunological studies) are also contradictory but suggest a reduced activity of NMDARs in the prefrontal, superior temporal cortex, anterior cingulate cortex, and hippocampus. CONCLUSIONS Glutamatergic transmission and NMDARs do not appear to be primarily involved in the pathophysiology of BD, but they might be linked to the severity and chronicity of the disorder. Disease progression could be associated with a long phase of enhanced glutamatergic transmission, with ensuing excitotoxicity and neuronal damage, resulting into a reduced density of functional NMDARs.
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Affiliation(s)
- Francesco Weiss
- Psychiatry 2 Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Valerio Caruso
- Psychiatry 2 Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Ugo De Rosa
- Psychiatry 2 Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Maria Francesca Beatino
- Psychiatry 2 Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Margherita Barbuti
- Psychiatry 2 Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Ferdinando Nicoletti
- Department of Physiology and Pharmacology, University Sapienza of Rome, Rome, Italy
- IRCCS Neuromed, Pozzilli, Italy
| | - Giulio Perugi
- Psychiatry 2 Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
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Carletti B, Banaj N, Piras F, Bossù P. Schizophrenia and Glutathione: A Challenging Story. J Pers Med 2023; 13:1526. [PMID: 38003841 PMCID: PMC10672475 DOI: 10.3390/jpm13111526] [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: 09/13/2023] [Revised: 10/13/2023] [Accepted: 10/20/2023] [Indexed: 11/26/2023] Open
Abstract
Schizophrenia (SZ) is a devastating mental illness with a complex and heterogeneous clinical state. Several conditions like symptoms, stage and severity of the disease are only some of the variables that have to be considered to define the disorder and its phenotypes. SZ pathophysiology is still unclear, and the diagnosis is currently relegated to the analysis of clinical symptoms; therefore, the search for biomarkers with diagnostic relevance is a major challenge in the field, especially in the era of personalized medicine. Though the mechanisms implicated in SZ are not fully understood, some processes are beginning to be elucidated. Oxidative stress, and in particular glutathione (GSH) dysregulation, has been demonstrated to play a crucial role in SZ pathophysiology. In fact, glutathione is a leading actor of oxidative-stress-mediated damage in SZ and appears to reflect the heterogeneity of the disease. The literature reports differing results regarding the levels of glutathione in SZ patients. However, each GSH state may be a sign of specific symptoms or groups of symptoms, candidating glutathione as a biomarker useful for discriminating SZ phenotypes. Here, we summarize the literature about the levels of glutathione in SZ and analyze the role of this molecule and its potential use as a biomarker.
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Affiliation(s)
- Barbara Carletti
- Laboratory of Neuropsychiatry, Clinical Neuroscience and Neurorehabilitation Department, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy; (N.B.); (F.P.)
| | - Nerisa Banaj
- Laboratory of Neuropsychiatry, Clinical Neuroscience and Neurorehabilitation Department, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy; (N.B.); (F.P.)
| | - Fabrizio Piras
- Laboratory of Neuropsychiatry, Clinical Neuroscience and Neurorehabilitation Department, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy; (N.B.); (F.P.)
| | - Paola Bossù
- Laboratory of Experimental Neuropsychobiology, Clinical Neuroscience and Neurorehabilitation Department, IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy;
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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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6
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Leung E, Lau EW, Liang A, de Dios C, Suchting R, Östlundh L, Masdeu JC, Fujita M, Sanches M, Soares JC, Selvaraj S. Alterations in brain synaptic proteins and mRNAs in mood disorders: a systematic review and meta-analysis of postmortem brain studies. Mol Psychiatry 2022; 27:1362-1372. [PMID: 35022529 DOI: 10.1038/s41380-021-01410-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 11/19/2021] [Accepted: 11/26/2021] [Indexed: 11/09/2022]
Abstract
The pathophysiological mechanisms underlying bipolar (BD) and major depressive disorders (MDD) are multifactorial but likely involve synaptic dysfunction and dysregulation. There are multiple synaptic proteins but three synaptic proteins, namely SNAP-25, PSD-95, and synaptophysin, have been widely studied for their role in synaptic function in human brain postmortem studies in BD and MDD. These studies have yielded contradictory results, possibly due to the small sample size and sourcing material from different cortical regions of the brain. We performed a systematic review and meta-analysis to understand the role of these three synaptic proteins and other synaptic proteins, messenger RNA (mRNA) and their regional localizations in BD and MDD. A systematic literature search was conducted and the review is reported in accordance with the MOOSE Guidelines. Meta-analysis was performed to compare synaptic marker levels between BD/MDD groups and controls separately. 1811 papers were identified in the literature search and screened against the preset inclusion and exclusion criteria. A total of 72 studies were screened in the full text, of which 47 were identified as eligible to be included in the systematic review. 24 of these 47 papers were included in the meta-analysis. The meta-analysis indicated that SNAP-25 protein levels were significantly lower in BD. On average, PSD-95 mRNA levels were lower in BD, and protein levels of SNAP-25, PSD-95, and syntaxin were lower in MDD. Localization analysis showed decreased levels of PSD-95 protein in the frontal cortex. We found specific alterations in synaptic proteins and RNAs in both BD and MDD. The review was prospectively registered online in PROSPERO international prospective register of systematic reviews, registration no. CRD42020196932.
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Affiliation(s)
- Edison Leung
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ethan W Lau
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Andi Liang
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Constanza de Dios
- Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Robert Suchting
- Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Linda Östlundh
- The National Medical Library, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Joseph C Masdeu
- Houston Methodist Neurological Institute, Houston, TX, USA.,Weill Cornell Medicine, New York, NY, USA
| | - Masahiro Fujita
- Weill Cornell Medicine, New York, NY, USA.,PET Core Facility, Houston Methodist Research Insitute, Houston, TX, USA
| | - Marsal Sanches
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jair C Soares
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Sudhakar Selvaraj
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA. .,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
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7
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Chen S, Alhassen W, Vakil Monfared R, Vachirakorntong B, Nauli SM, Baldi P, Alachkar A. Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan. Int J Mol Sci 2021; 22:10387. [PMID: 34638726 PMCID: PMC8509004 DOI: 10.3390/ijms221910387] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 12/27/2022] Open
Abstract
Almost all brain cells contain primary cilia, antennae-like microtubule sensory organelles, on their surface, which play critical roles in brain functions. During neurodevelopmental stages, cilia are essential for brain formation and maturation. In the adult brain, cilia play vital roles as signaling hubs that receive and transduce various signals and regulate cell-to-cell communications. These distinct roles suggest that cilia functions, and probably structures, change throughout the human lifespan. To further understand the age-dependent changes in cilia roles, we identified and analyzed age-dependent patterns of expression of cilia's structural and functional components across the human lifespan. We acquired cilia transcriptomic data for 16 brain regions from the BrainSpan Atlas and analyzed the age-dependent expression patterns using a linear regression model by calculating the regression coefficient. We found that 67% of cilia transcripts were differentially expressed genes with age (DEGAs) in at least one brain region. The age-dependent expression was region-specific, with the highest and lowest numbers of DEGAs expressed in the ventrolateral prefrontal cortex and hippocampus, respectively. The majority of cilia DEGAs displayed upregulation with age in most of the brain regions. The transcripts encoding cilia basal body components formed the majority of cilia DEGAs, and adjacent cerebral cortices exhibited large overlapping pairs of cilia DEGAs. Most remarkably, specific α/β-tubulin subunits (TUBA1A, TUBB2A, and TUBB2B) and SNAP-25 exhibited the highest rates of downregulation and upregulation, respectively, across age in almost all brain regions. α/β-tubulins and SNAP-25 expressions are known to be dysregulated in age-related neurodevelopmental and neurodegenerative disorders. Our results support a role for the high dynamics of cilia structural and functional components across the lifespan in the normal physiology of brain circuits. Furthermore, they suggest a crucial role for cilia signaling in the pathophysiological mechanisms of age-related psychiatric/neurological disorders.
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Affiliation(s)
- Siwei Chen
- Department of Computer Science, School of Information and Computer Sciences, University of California-Irvine, Irvine, CA 92617, USA; (S.C.); (P.B.)
- Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California-Irvine, Irvine, CA 92617, USA
| | - Wedad Alhassen
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California-Irvine, Irvine, CA 92617, USA; (W.A.); (R.V.M.); (B.V.)
| | - Roudabeh Vakil Monfared
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California-Irvine, Irvine, CA 92617, USA; (W.A.); (R.V.M.); (B.V.)
| | - Benjamin Vachirakorntong
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California-Irvine, Irvine, CA 92617, USA; (W.A.); (R.V.M.); (B.V.)
| | - Surya M. Nauli
- Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University Rinker Health Science Campus, Irvine, CA 92618, USA;
| | - Pierre Baldi
- Department of Computer Science, School of Information and Computer Sciences, University of California-Irvine, Irvine, CA 92617, USA; (S.C.); (P.B.)
- Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California-Irvine, Irvine, CA 92617, USA
| | - Amal Alachkar
- Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California-Irvine, Irvine, CA 92617, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California-Irvine, Irvine, CA 92617, USA; (W.A.); (R.V.M.); (B.V.)
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8
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Blasi V, Bolognesi E, Ricci C, Baglio G, Zanzottera M, Canevini MP, Walder M, Cabinio M, Zanette M, Baglio F, Clerici M, Guerini FR. SNAP-25 Single Nucleotide Polymorphisms, Brain Morphology and Intelligence in Children With Borderline Intellectual Functioning: A Mediation Analysis. Front Neurosci 2021; 15:715048. [PMID: 34512248 PMCID: PMC8427043 DOI: 10.3389/fnins.2021.715048] [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: 05/26/2021] [Accepted: 08/04/2021] [Indexed: 11/13/2022] Open
Abstract
Borderline intellectual functioning (BIF) is a multifactorial condition in which both genetic and environmental factors are likely to contribute to the clinical outcome. Abnormal cortical development and lower IQ scores were shown to be correlated in BIF children, but the genetic components of this condition and their possible connection with intelligence and brain morphology have never been investigated in BIF. The synaptosomal-associated protein of 25 kD (SNAP-25) is involved in synaptic plasticity, neural maturation, and neurotransmission, affecting intellectual functioning. We investigated SNAP-25 polymorphisms in BIF and correlated such polymorphisms with intelligence and cortical thickness, using socioeconomic status and environmental stress as covariates as a good proxy of the variables that determine intellectual abilities. Thirty-three children with a diagnosis of BIF were enrolled in the study. SNAP-25 polymorphisms rs363050, rs363039, rs363043, rs3746544, and rs1051312 were analyzed by genotyping; cortical thickness was studied by MRI; intelligence was measured using the WISC-III/IV subscales; environmental stressors playing a role in neuropsychiatric development were considered as covariate factors. Results showed that BIF children carrying the rs363043(T) minor allele represented by (CT + TT) genotypes were characterized by lower performance Perceptual Reasoning Index and lower full-scale IQ scores (p = 0.04) compared to those carrying the (CC) genotype. This association was correlated with a reduced thickness of the left inferior parietal cortex (direct effect = 0.44) and of the left supramarginal gyrus (direct effect = 0.56). These results suggest a link between SNAP-25 polymorphism and intelligence with the mediation role of brain morphological features in children with BIF.
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Affiliation(s)
- Valeria Blasi
- IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy
| | | | - Cristian Ricci
- Pediatric Epidemiology, Department of Pediatrics, Medical Faculty, Leipzig University, Leipzig, Germany
| | | | | | - Maria Paola Canevini
- Epilepsy Center, ASST S. Paolo and S. Carlo Hospital, Milan, Italy.,Department of Health Sciences, University of Milan, Milan, Italy
| | - Mauro Walder
- Child Neuropsychiatry Unit - ASST S. Paolo and S. Carlo Hospital, Milan, Italy
| | - Monia Cabinio
- IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy
| | | | | | - Mario Clerici
- IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy.,Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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9
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Insights into the Pathophysiology of Psychiatric Symptoms in Central Nervous System Disorders: Implications for Early and Differential Diagnosis. Int J Mol Sci 2021; 22:ijms22094440. [PMID: 33922780 PMCID: PMC8123079 DOI: 10.3390/ijms22094440] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/16/2021] [Accepted: 04/21/2021] [Indexed: 12/12/2022] Open
Abstract
Different psychopathological manifestations, such as affective, psychotic, obsessive-compulsive symptoms, and impulse control disturbances, may occur in most central nervous system (CNS) disorders including neurodegenerative and neuroinflammatory diseases. Psychiatric symptoms often represent the clinical onset of such disorders, thus potentially leading to misdiagnosis, delay in treatment, and a worse outcome. In this review, psychiatric symptoms observed along the course of several neurological diseases, namely Alzheimer’s disease, fronto-temporal dementia, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, are discussed, as well as the involved brain circuits and molecular/synaptic alterations. Special attention has been paid to the emerging role of fluid biomarkers in early detection of these neurodegenerative diseases. The frequent occurrence of psychiatric symptoms in neurological diseases, even as the first clinical manifestations, should prompt neurologists and psychiatrists to share a common clinico-biological background and a coordinated diagnostic approach.
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10
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Santa-Marinha L, Castanho I, Silva RR, Bravo FV, Miranda AM, Meira T, Morais-Ribeiro R, Marques F, Xu Y, Point du Jour K, Wenk M, Chan RB, Di Paolo G, Pinto V, Oliveira TG. Phospholipase D1 Ablation Disrupts Mouse Longitudinal Hippocampal Axis Organization and Functioning. Cell Rep 2021; 30:4197-4208.e6. [PMID: 32209478 DOI: 10.1016/j.celrep.2020.02.102] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 01/29/2020] [Accepted: 02/27/2020] [Indexed: 01/01/2023] Open
Abstract
Phosphatidic acid (PA) is a signaling lipid involved in the modulation of synaptic structure and functioning. Based on previous work showing a decreasing PA gradient along the longitudinal axis of the rodent hippocampus, we asked whether the dorsal hippocampus (DH) and the ventral hippocampus (VH) are differentially affected by PA modulation. Here, we show that phospholipase D1 (PLD1) is a major hippocampal PA source, compared to PLD2, and that PLD1 ablation affects predominantly the lipidome of the DH. Moreover, Pld1 knockout (KO) mice show specific deficits in novel object recognition and social interaction and disruption in the DH-VH dendritic arborization differentiation in CA1/CA3 pyramidal neurons. Also, Pld1 KO animals present reduced long-term depression (LTD) induction and reduced GluN2A and SNAP-25 protein levels in the DH. Overall, we observe that PLD1-derived PA reduction leads to differential lipid signatures along the longitudinal hippocampal axis, predominantly affecting DH organization and functioning.
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Affiliation(s)
- Luísa Santa-Marinha
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Isabel Castanho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rita Ribeiro Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Francisca Vaz Bravo
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - André Miguel Miranda
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Torcato Meira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rafaela Morais-Ribeiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Fernanda Marques
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Yimeng Xu
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
| | - Kimberly Point du Jour
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA
| | - Markus Wenk
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore
| | - Robin Barry Chan
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA
| | - Gilbert Di Paolo
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA
| | - Vítor Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Tiago Gil Oliveira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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11
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Chen F, Chen H, Chen Y, Wei W, Sun Y, Zhang L, Cui L, Wang Y. Dysfunction of the SNARE complex in neurological and psychiatric disorders. Pharmacol Res 2021; 165:105469. [PMID: 33524541 DOI: 10.1016/j.phrs.2021.105469] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/30/2020] [Accepted: 01/24/2021] [Indexed: 02/07/2023]
Abstract
The communication between neurons constitutes the basis of all neural activities, and synaptic vesicle exocytosis is the fundamental biological event that mediates most communication between neurons in the central nervous system. The SNARE complex is the core component of the protein machinery that facilitates the fusion of synaptic vesicles with presynaptic terminals and thereby the release of neurotransmitters. In synapses, each release event is dependent on the assembly of the SNARE complex. In recent years, basic research on the SNARE complex has provided a clearer understanding of the mechanism underlying the formation of the SNARE complex and its role in vesicle formation. Emerging evidence indicates that abnormal expression or dysfunction of the SNARE complex in synapse physiology might contribute to abnormal neurotransmission and ultimately to synaptic dysfunction. Clinical research using postmortem tissues suggests that SNARE complex dysfunction is correlated with various neurological diseases, and some basic research has also confirmed the important role of the SNARE complex in the pathology of these diseases. Genetic and pharmacogenetic studies suggest that the SNARE complex and individual proteins might represent important molecular targets in neurological disease. In this review, we summarize the recent progress toward understanding the SNARE complex in regulating membrane fusion events and provide an update of the recent discoveries from clinical and basic research on the SNARE complex in neurodegenerative, neuropsychiatric, and neurodevelopmental diseases.
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Affiliation(s)
- Feng Chen
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Huiyi Chen
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yanting Chen
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Wenyan Wei
- Department of Gerontology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yuanhong Sun
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Lu Zhang
- The First Clinical College, Guangdong Medical University, Zhanjiang, China
| | - Lili Cui
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
| | - Yan Wang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China; Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiao tong University, Xi'an, China.
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12
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Systems biology reveals reprogramming of the S-nitroso-proteome in the cortical and striatal regions of mice during aging process. Sci Rep 2020; 10:13913. [PMID: 32807865 PMCID: PMC7431412 DOI: 10.1038/s41598-020-70383-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 07/28/2020] [Indexed: 12/26/2022] Open
Abstract
Cell aging depends on the rate of cumulative oxidative and nitrosative damage to DNA and proteins. Accumulated data indicate the involvement of protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification (PTM) of cysteine thiols, in different brain disorders. However, the changes and involvement of SNO in aging including the development of the organism from juvenile to adult state is still unknown. In this study, using the state-of-the-art mass spectrometry technology to identify S-nitrosylated proteins combined with large-scale computational biology, we tested the S-nitroso-proteome in juvenile and adult mice in both cortical and striatal regions. We found reprogramming of the S-nitroso-proteome in adult mice of both cortex and striatum regions. Significant biological processes and protein–protein clusters associated with synaptic and neuronal terms were enriched in adult mice. Extensive quantitative analysis revealed a large set of potentially pathological proteins that were significantly upregulated in adult mice. Our approach, combined with large scale computational biology allowed us to perform a system-level characterization and identification of the key proteins and biological processes that can serve as drug targets for aging and brain disorders in future studies.
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13
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Nazeri A, Schifani C, Anderson JAE, Ameis SH, Voineskos AN. In Vivo Imaging of Gray Matter Microstructure in Major Psychiatric Disorders: Opportunities for Clinical Translation. BIOLOGICAL PSYCHIATRY: COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2020; 5:855-864. [PMID: 32381477 DOI: 10.1016/j.bpsc.2020.03.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 03/06/2020] [Accepted: 03/06/2020] [Indexed: 12/11/2022]
Abstract
Postmortem studies reveal that individuals with major neuropsychiatric disorders such as schizophrenia and autism spectrum disorder have gray matter microstructural abnormalities. These include abnormalities in neuropil organization, expression of proteins supporting neuritic and synaptic integrity, and myelination. Genetic and postmortem studies suggest that these changes may be causally linked to the pathogenesis of these disorders. Advances in diffusion-weighted magnetic resonance image (dMRI) acquisition techniques and biophysical modeling allow for the quantification of gray matter microstructure in vivo. While several biophysical models for imaging microstructural properties are available, one in particular, neurite orientation dispersion and density imaging (NODDI), holds great promise for clinical applications. NODDI can be applied to both gray and white matter and requires only a single extra shell beyond a standard dMRI acquisition. Since its development only a few years ago, the NODDI algorithm has been used to characterize gray matter microstructure in schizophrenia, Alzheimer's disease, healthy aging, and development. These investigations have shown that microstructural findings in vivo, using NODDI, align with postmortem findings. Not only do NODDI and other advanced dMRI-based modeling methods provide a window into the brain previously only available postmortem, but they may be more sensitive to certain brain changes than conventional magnetic resonance imaging approaches. This opens up exciting new possibilities for clinicians to more rapidly detect disease signatures and allows earlier intervention in the course of the disease. Given that neurites and gray matter microstructure have the capacity to rapidly remodel, these novel dMRI-based methods represent an opportunity to noninvasively monitor neuroplastic changes posttherapy within much shorter time scales.
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Affiliation(s)
- Arash Nazeri
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
| | - Christin Schifani
- Kimel Family Translational Imaging Genetics Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
| | - John A E Anderson
- Kimel Family Translational Imaging Genetics Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
| | - Stephanie H Ameis
- Margaret and Wallace McCain Centre for Child, Youth and Family Mental Health, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Centre for Brain and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Aristotle N Voineskos
- Kimel Family Translational Imaging Genetics Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
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14
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Bobilev AM, Perez JM, Tamminga CA. Molecular alterations in the medial temporal lobe in schizophrenia. Schizophr Res 2020; 217:71-85. [PMID: 31227207 DOI: 10.1016/j.schres.2019.06.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/29/2019] [Accepted: 06/01/2019] [Indexed: 11/30/2022]
Abstract
The medial temporal lobe (MTL) and its individual structures have been extensively implicated in schizophrenia pathophysiology, with considerable efforts aimed at identifying structural and functional differences in this brain region. The major structures of the MTL for which prominent differences have been revealed include the hippocampus, the amygdala and the superior temporal gyrus (STG). The different functions of each of these regions have been comprehensively characterized, and likely contribute differently to schizophrenia. While neuroimaging studies provide an essential framework for understanding the role of these MTL structures in various aspects of the disease, ongoing efforts have sought to employ molecular measurements in order to elucidate the biology underlying these macroscopic differences. This review provides a summary of the molecular findings in three major MTL structures, and discusses convergent findings in cellular architecture and inter-and intra-cellular networks. The findings of this effort have uncovered cell-type, network and gene-level specificity largely unique to each brain region, indicating distinct molecular origins of disease etiology. Future studies should test the functional implications of these molecular changes at the circuit level, and leverage new advances in sequencing technology to further refine our understanding of the differential contribution of MTL structures to schizophrenia.
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Affiliation(s)
- Anastasia M Bobilev
- Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, United States of America.
| | - Jessica M Perez
- Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, United States of America.
| | - Carol A Tamminga
- Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, United States of America.
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15
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Interaction of Synaptosomal-Associated Protein 25 with Neutral Sphingomyelinase 2: Functional Impact on the Sphingomyelin Pathway. Neuroscience 2020; 427:1-15. [PMID: 31765623 DOI: 10.1016/j.neuroscience.2019.08.015] [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: 03/19/2019] [Revised: 08/06/2019] [Accepted: 08/07/2019] [Indexed: 11/22/2022]
Abstract
Neurotransmitter release is mediated by ceramide, which is generated by sphingomyelin hydrolysis. In the present study, we examined whether synaptosomal-associated protein 25 (SNAP-25) is involved in ceramide production and exocytosis. Neutral sphingomyelinase 2 (nSMase2) was partially purified from bovine brain and we found that SNAP-25 was enriched in the nSMase2-containing fractions. In rat synaptosomes and PC12 cells, the immunoprecipitation pellet of anti-SNAP-25 antibody showed higher nSMase activity than the immunoprecipitation pellet of anti-nSMase2 antibody. In PC12 cells, SNAP-25 was colocalized with nSMase2. Transfection of SNAP-25 small interfering RNA (siRNA) significantly inhibited nSMase2 translocation to the plasma membrane. A23187-induced ceramide production was concomitantly reduced in SNAP-25 siRNA-transfected PC12 cells compared with that in scrambled siRNA-transfected cells. Moreover, transfection of SNAP-25 siRNA inhibited dopamine release, whereas addition of C6-ceramide to the siRNA-treated cells moderately reversed this inhibition. Additionally, nSMase2 inhibition reduced dopamine release. Collectively, our results indicate that SNAP-25 interacts with nSMase2 during ceramide production, which mediates exocytosis and neurotransmitter release.
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16
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Kazantseva AV, Enikeeva RF, Romanova AR, Malykh SB, Galyautdinova SI, Khusnutdinova EK. Stress-Associated Cognitive Functioning Is Controlled by Variations in Synaptic Plasticity Genes. RUSS J GENET+ 2020. [DOI: 10.1134/s1022795420010068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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17
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Gigg J, McEwan F, Smausz R, Neill J, Harte MK. Synaptic biomarker reduction and impaired cognition in the sub-chronic PCP mouse model for schizophrenia. J Psychopharmacol 2020; 34:115-124. [PMID: 31580184 DOI: 10.1177/0269881119874446] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Sub-chronic phencyclidine treatment (scPCP) provides a translational rat model for cognitive impairments associated with schizophrenia (CIAS). CIAS genetic risk factors may be more easily studied in mice; however, CIAS associated biomarker changes are relatively unstudied in the scPCP mouse. AIM To characterize deficits in object recognition memory and synaptic markers in frontal cortex and hippocampus of the scPCP mouse. METHODS Female c57/bl6 mice received 10 daily injections of PCP (scPCP; 10 mg/kg, s.c.) or vehicle (n = 8/group). Mice were tested for novel object recognition memory after either remaining in the arena ('no distraction') or being removed to a holding cage ('distraction') during the inter-trial interval. Expression changes for parvalbumin (PV), glutamic acid decarboxylase (GAD67), synaptosomal-associated protein 25 (SNAP-25) and postsynaptic density 95 (PDS95) were measured in frontal cortex, dorsal and ventral hippocampus. RESULTS scPCP mice showed object memory deficits when distracted by removal from the arena, where they treated previously experienced objects as novel at test. scPCP significantly reduced PV expression in all regions and lower PSD95 levels in frontal cortex and ventral hippocampus. Levels of GAD67 and SNAP-25 were unchanged. CONCLUSIONS We show for the first time that scPCP mice: (a) can encode and retain object information, but that this memory is susceptible to distraction; (b) display amnesia after distraction; and (c) express reduced PV and PSD95 in frontal cortex and hippocampus. These data further support reductions in PV-dependent synaptic inhibition and NMDAR-dependent glutamatergic plasticity in CIAS and highlight the translational significance of the scPCP mouse.
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Affiliation(s)
- John Gigg
- Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK
| | - Francesca McEwan
- Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK
| | - Rebecca Smausz
- Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK
| | - Joanna Neill
- Division of Pharmacy and Optometry, University of Manchester, Manchester, UK
| | - Michael K Harte
- Division of Pharmacy and Optometry, University of Manchester, Manchester, UK
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18
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Guan F, Zhang T, Han W, Zhu L, Ni T, Lin H, Liu D, Chen G, Xiao J, Li T. Relationship of SNAP25 variants with schizophrenia and antipsychotic-induced weight change in large-scale schizophrenia patients. Schizophr Res 2020; 215:250-255. [PMID: 31653583 DOI: 10.1016/j.schres.2019.09.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 05/19/2019] [Accepted: 09/23/2019] [Indexed: 01/16/2023]
Abstract
The SNAP25 gene is involved in the development of antipsychotic-induced weight gain (AIWG) or metabolic syndrome during antipsychotics use in Americans and Europeans, but its role in Asians remains unknown. To identify common variants in SNAP25 associated with schizophrenia and evaluate their effects on AIWG and antipsychotic responses in Han Chinese individuals with schizophrenia, we conducted a two-stage case-control study of 3,243 patients and 6,154 healthy controls. 2128 inpatients in the replication stage have received conventional treatment with an antipsychotic monotherapy (Haloperidol, Olanzapine or Risperidone) for 10 weeks at least. Weight change, antipsychotic responses and metabolic indices change were assessed during treatments. Three SNPs were significantly associated with schizophrenia in samples (rs6039769, P = 6.64 × 10-7; rs3787283, P = 0.004283; rs3746544, P = 2.51 × 10-6). Of these, rs6039769 is a novel schizophrenia-associated SNP and is uncorrelated with the other two variants, which have previously been associated with schizophrenia in European-ancestry samples. Rs6039769 was significantly associated with AIWG (P < 0.001), but not with antipsychotic responses or metabolic indices. Another two SNPs were not associated with AIWG or antipsychotic responses or metabolic indices. Overall, there were significant differences in antipsychotic responses and metabolic indices among the three treatment groups. Our findings suggest that SNAP25 gene may contribute to the susceptibility of AIWG and even metabolic disturbances. A prior identification of high-risk of patients with rs6039769 would contribute to a better precision of the pharmacological treatment.
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Affiliation(s)
- Fanglin Guan
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Tianxiao Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Wei Han
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Li Zhu
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Tong Ni
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Huali Lin
- Xi'an Mental Health Center, 15 Yanyin Road, Xi'an, Shaanxi, 710086, China
| | - Dan Liu
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Gang Chen
- Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Department of Forensic Pathology, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Jing Xiao
- Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Department of Forensic Pathology, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Tao Li
- Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Department of Forensic Pathology, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China.
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19
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The SNAP-25 Protein Family. Neuroscience 2019; 420:50-71. [DOI: 10.1016/j.neuroscience.2018.09.020] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 08/31/2018] [Accepted: 09/14/2018] [Indexed: 01/04/2023]
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20
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SNAP-25 in Major Psychiatric Disorders: A Review. Neuroscience 2019; 420:79-85. [PMID: 30790667 DOI: 10.1016/j.neuroscience.2019.02.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 01/10/2019] [Accepted: 02/07/2019] [Indexed: 02/07/2023]
Abstract
Synaptosomal Associated Protein-25 kilodaltons (SNAP-25) is an integral member of the SNARE complex. This complex is essential for calcium-triggered synaptic vesicular fusion and release of neurotransmitters into the synaptic cleft. In addition to neurotransmission, SNAP-25 is associated with insulin release, the regulation of intracellular calcium, and neuroplasticity. Because of SNAP-25's varied and crucial biological roles, the consequences of changes in this protein can be seen in both the central nervous system and the periphery. In this review, we will look at the published literature from human genetic, postmortem, and animal studies involving SNAP-25. The accumulated data indicate that SNAP-25 may be linked with some symptoms associated with a variety of psychiatric disorders. These disorders include bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder, autism, alcohol use disorder, and dementia. There are also data suggesting SNAP-25 may be involved with non-psychiatric seizures and metabolic disorders. We believe investigation of SNAP-25 is important for understanding both normal behavior and some aspects of the pathophysiology of behavior seen with psychiatric disorders. The wealth of information from both animal and human studies on SNAP-25 offers an excellent opportunity to use a bi-directional research approach. Hypotheses generated from genetically manipulated mice can be directly tested in human postmortem tissue, and, conversely, human genetic and postmortem findings can improve and validate animal models for psychiatric disorders.
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Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels. Proteomes 2019; 7:proteomes7010005. [PMID: 30678040 PMCID: PMC6473632 DOI: 10.3390/proteomes7010005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 01/16/2019] [Accepted: 01/17/2019] [Indexed: 12/18/2022] Open
Abstract
Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, which is a group of proteins involved in neuronal ion channel regulation and synaptic transmission. We previously demonstrated that male Fgf14−/− mice recapitulate the salient endophenotypes of synaptic dysfunction and behaviors that are associated with schizophrenia (SZ). As the underlying etiology of SZ and its sex-specific onset remain elusive, the Fgf14−/− model may provide a valuable tool to interrogate pathways related to disease mechanisms. Here, we performed label-free quantitative proteomics to identify enriched pathways in both male and female hippocampi from Fgf14+/+ and Fgf14−/− mice. We discovered that all of the differentially expressed proteins measured in Fgf14−/− animals, relative to their same-sex wildtype counterparts, are associated with SZ based on genome-wide association data. In addition, measured changes in the proteome were predominantly sex-specific, with the male Fgf14−/− mice distinctly enriched for pathways associated with neuropsychiatric disorders. In the male Fgf14−/− mouse, we found molecular characteristics that, in part, may explain a previously described neurotransmission and behavioral phenotype. This includes decreased levels of ALDH1A1 and protein kinase A (PRKAR2B). ALDH1A1 has been shown to mediate an alternative pathway for gamma-aminobutyric acid (GABA) synthesis, while PRKAR2B is essential for dopamine 2 receptor signaling, which is the basis of current antipsychotics. Collectively, our results provide new insights in the role of FGF14 and support the use of the Fgf14−/− mouse as a useful preclinical model of SZ for generating hypotheses on disease mechanisms, sex-specific manifestation, and therapy.
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Lleó A, Parnetti L, Belbin O, Wiltfang J. Has the time arrived for cerebrospinal fluid biomarkers in psychiatric disorders? Clin Chim Acta 2019; 491:81-84. [PMID: 30682327 DOI: 10.1016/j.cca.2019.01.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 01/16/2019] [Accepted: 01/18/2019] [Indexed: 01/13/2023]
Abstract
Psychiatric disorders are currently classified, in the majority of cases, by clinical syndromes. However, advances over the last decade in imaging and biochemical biomarkers in several Central Nervous System (CNS) disorders anticipate the incorporation of some of these markers in the diagnostic work-up of psychiatric conditions. In particular, CSF biomarkers offer the possibility of detecting a wide range of pathophysiological processes in the CNS. Newer CSF markers can measure axonal and synaptic damage, glial activation, and oxidative stress in CNS disorders with high precision. The possibility that these markers can be applied in the differential diagnosis of common psychiatric disorders such as Schizophrenia, Major Depressive or Bipolar Disorders not only to rule out neurodegenerative diseases but also to identify specific biomarker signatures has yet to be explored. In particular, synaptic proteins in CSF could be useful as markers of synaptic and neurotransmitter transmission impairment since these are key molecular features of psychiatric conditions. In this paper we outline the current and potential applications of CSF biomarkers in psychiatric disorders.
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Affiliation(s)
- Alberto Lleó
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
| | - Lucilla Parnetti
- Centre for Memory Disturbances, Section of Neurology, Lab of Clinical Neurochemistry, University of Perugia, Perugia, Italy
| | - Olivia Belbin
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Jens Wiltfang
- Department of Psychiatry and Psychotherapy, University Medical Center Goettingen (UMG), Goettingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany
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Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures. Mol Psychiatry 2019; 24:549-561. [PMID: 29511299 PMCID: PMC6004314 DOI: 10.1038/s41380-018-0041-5] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 01/05/2018] [Accepted: 01/31/2018] [Indexed: 02/06/2023]
Abstract
Although synaptic loss is thought to be core to the pathophysiology of schizophrenia, the nature, consistency and magnitude of synaptic protein and mRNA changes has not been systematically appraised. Our objective was thus to systematically review and meta-analyse findings. The entire PubMed database was searched for studies from inception date to the 1st of July 2017. We selected case-control postmortem studies in schizophrenia quantifying synaptic protein or mRNA levels in brain tissue. The difference in protein and mRNA levels between cases and controls was extracted and meta-analysis conducted. Among the results, we found a significant reduction in synaptophysin in schizophrenia in the hippocampus (effect size: -0.65, p < 0.01), frontal (effect size: -0.36, p = 0.04), and cingulate cortices (effect size: -0.54, p = 0.02), but no significant changes for synaptophysin in occipital and temporal cortices, and no changes for SNAP-25, PSD-95, VAMP, and syntaxin in frontal cortex. There were insufficient studies for meta-analysis of complexins, synapsins, rab3A and synaptotagmin and mRNA measures. Findings are summarised for these, which generally show reductions in SNAP-25, PSD-95, synapsin and rab3A protein levels in the hippocampus but inconsistency in other regions. Our findings of moderate-large reductions in synaptophysin in hippocampus and frontal cortical regions, and a tendency for reductions in other pre- and postsynaptic proteins in the hippocampus are consistent with models that implicate synaptic loss in schizophrenia. However, they also identify potential differences between regions and proteins, suggesting synaptic loss is not uniform in nature or extent.
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24
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Cognitive impairments associated with alterations in synaptic proteins induced by the genetic loss of adenosine A 2A receptors in mice. Neuropharmacology 2017; 126:48-57. [DOI: 10.1016/j.neuropharm.2017.08.027] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 07/28/2017] [Accepted: 08/17/2017] [Indexed: 12/15/2022]
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A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia. J Neurosci 2017; 37:10389-10397. [PMID: 28972123 DOI: 10.1523/jneurosci.1040-17.2017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 09/08/2017] [Accepted: 09/13/2017] [Indexed: 12/16/2022] Open
Abstract
The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25, rs6039769, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b/SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.
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Ghasemi M, Phillips C, Fahimi A, McNerney MW, Salehi A. Mechanisms of action and clinical efficacy of NMDA receptor modulators in mood disorders. Neurosci Biobehav Rev 2017; 80:555-572. [DOI: 10.1016/j.neubiorev.2017.07.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 06/23/2017] [Accepted: 07/08/2017] [Indexed: 12/22/2022]
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27
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Neuroadaptations to antipsychotic drugs: Insights from pre-clinical and human post-mortem studies. Neurosci Biobehav Rev 2017; 76:317-335. [DOI: 10.1016/j.neubiorev.2016.10.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 07/07/2016] [Accepted: 10/06/2016] [Indexed: 12/21/2022]
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Li YC, Kavalali ET. Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets. Pharmacol Rev 2017; 69:141-160. [PMID: 28265000 PMCID: PMC5394918 DOI: 10.1124/pr.116.013342] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Presynaptic nerve terminals are highly specialized vesicle-trafficking machines. Neurotransmitter release from these terminals is sustained by constant local recycling of synaptic vesicles independent from the neuronal cell body. This independence places significant constraints on maintenance of synaptic protein complexes and scaffolds. Key events during the synaptic vesicle cycle-such as exocytosis and endocytosis-require formation and disassembly of protein complexes. This extremely dynamic environment poses unique challenges for proteostasis at synaptic terminals. Therefore, it is not surprising that subtle alterations in synaptic vesicle cycle-associated proteins directly or indirectly contribute to pathophysiology seen in several neurologic and psychiatric diseases. In contrast to the increasing number of examples in which presynaptic dysfunction causes neurologic symptoms or cognitive deficits associated with multiple brain disorders, synaptic vesicle-recycling machinery remains an underexplored drug target. In addition, irrespective of the involvement of presynaptic function in the disease process, presynaptic machinery may also prove to be a viable therapeutic target because subtle alterations in the neurotransmitter release may counter disease mechanisms, correct, or compensate for synaptic communication deficits without the need to interfere with postsynaptic receptor signaling. In this article, we will overview critical properties of presynaptic release machinery to help elucidate novel presynaptic avenues for the development of therapeutic strategies against neurologic and neuropsychiatric disorders.
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Affiliation(s)
- Ying C Li
- Departments of Neuroscience (Y.C.L., E.T.K.) and Physiology (E.T.K.), University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ege T Kavalali
- Departments of Neuroscience (Y.C.L., E.T.K.) and Physiology (E.T.K.), University of Texas Southwestern Medical Center, Dallas, Texas
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29
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Huang CJ, Lee CL, Liu CY, Huang SH, Hou JW, Chen YH, Chien CC, Ho CM, Lo WC, Hung KL. Detection of lower levels of SNAP25 using multiple microarray systems and its functional significance in medulloblastoma. Int J Mol Med 2017; 39:1195-1205. [PMID: 28339008 PMCID: PMC5403484 DOI: 10.3892/ijmm.2017.2925] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 03/09/2017] [Indexed: 01/01/2023] Open
Abstract
Medulloblastoma (MB) is the most common pediatric malignant brain tumor and patients with high-risk or recurrent MB respond poorly to current therapies, and have a higher related mortality. For this reason, potential molecules related to MB need be identified in order to develop targets for the development of novel therapeutics. In the present study, we compared MB microarray data obtained using different microarray systems and significant targets were selected by gene annotation and enrichment analysis. Genes for soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) annotated with the function 'vesicle' were identified and one of these proteins, synaptosomal-associated protein 25 (SNAP25), was found to have significantly lower expression levels in MB. In addition, SNAP25 was detected in a very low number of MB cells as shown by western blot analysis and immunohistochemical analyses of archived and formalin-fixed/paraffin-embedded human MB specimens. We found that SNAP25 altered the morphology and the chemotherapeutic effects of arabinofuranosyl cytidine (Ara-C) on SNAP25-expressing MB cells. On the whole, our data indicate that the expression of SNAP25 is crucial for dendrite formation and is associated with the effects of targeted chemotherapy. The detection of SNAP25 expression in MB cells may thus be essential for the chemotherapeutic application of Ara-C.
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Affiliation(s)
- Chi-Jung Huang
- Department of Biochemistry, National Defense Medical Center, Taipei 11490, Taiwan, R.O.C
| | - Chia-Long Lee
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Chih-Yi Liu
- Department of Pathology, Sijhih Cathay General Hospital, New Taipei 22174, Taiwan, R.O.C
| | - Shih-Hung Huang
- Department of Pathology, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C
| | - Jia-Woei Hou
- Department of Pediatrics, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C
| | - Yi-Hou Chen
- Department of Medical Research, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C
| | - Chih-Cheng Chien
- Department of Medical Research, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C
| | - Chih-Ming Ho
- Department of Medical Research, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C
| | - Wen-Cheng Lo
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C
| | - Kun-Long Hung
- Department of Pediatrics, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C
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30
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Zieminska E, Lenart J, Lazarewicz JW. Select putative neurodevelopmental toxins modify SNAP-25 expression in primary cultures of rat cerebellar granule cells. Toxicology 2016; 370:86-93. [PMID: 27693314 DOI: 10.1016/j.tox.2016.09.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 09/22/2016] [Accepted: 09/26/2016] [Indexed: 11/19/2022]
Abstract
A presynaptic protein SNAP-25 belonging to SNARE complex which is instrumental in intracellular vesicular trafficking and exocytosis, has been implicated in hyperactivity and cognitive abilities in some neuropsychiatric disorders. The unclear etiology of the behavior disrupting neurodevelopmental disabilities in addition to genetic causes most likely involves environmental factors. The aim of this in vitro study was to test if various suspected developmental neurotoxins can alter SNAP-25 mRNA and protein expression in neurons. Real-time PCR and Western blotting analyses were used to assess SNAP-25 mRNA and protein levels in primary cultures of rat cerebellar granule cells (CGCs). The test substances: tetrabromobisphenol-A (TBBPA), thimerosal (TH), silver nanoparticles (NAg), valproic acid (VPA) and thalidomide (THAL), were administered to CGC cultures at subtoxic concentrations for 24h. The results demonstrated that SNAP-25 mRNA levels were increased by 49 and 66% by TBBPA and THAL, respectively, whereas VPA and NAg reduced these levels to 48 and 64% of the control, respectively. The SNAP-25 protein content in CGCs was increased by 79% by TBBPA, 25% by THAL and 21% by NAg; VPA and TH reduced these levels to 73 and 69% of the control, respectively. The variety of changes in SNAP-25 expression on mRNA and protein level suggests the diversity of the mechanism of action of the test substances. This initial study provided no data on concentration-effect relations and on functional changes in CGCs. However it is the first to demonstrate the effect of different compounds that are suspected of causing neurodevelopmental disabilities on SNAP-25 expression. These results suggest that this protein may be a common target for not only inherited but also environmental modifications linked to behavioral deficits in neurodevelopmental disabilities.
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Affiliation(s)
- Elzbieta Zieminska
- Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
| | - Jacek Lenart
- Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
| | - Jerzy W Lazarewicz
- Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
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31
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Abstract
Schizophrenia is a serious psychiatric illness which is experienced by about 1 % of individuals worldwide and has a debilitating impact on perception, cognition, and social function. Over the years, several models/hypotheses have been developed which link schizophrenia to dysregulations of the dopamine, glutamate, and serotonin receptor pathways. An important segment of these pathways that have been extensively studied for the pathophysiology of schizophrenia is the presynaptic neurotransmitter release mechanism. This set of molecular events is an evolutionarily well-conserved process that involves vesicle recruitment, docking, membrane fusion, and recycling, leading to efficient neurotransmitter delivery at the synapse. Accumulated evidence indicate dysregulation of this mechanism impacting postsynaptic signal transduction via different neurotransmitters in key brain regions implicated in schizophrenia. In recent years, after ground-breaking work that elucidated the operations of this mechanism, research efforts have focused on the alterations in the messenger RNA (mRNA) and protein expression of presynaptic neurotransmitter release molecules in schizophrenia and other neuropsychiatric conditions. In this review article, we present recent evidence from schizophrenia human postmortem studies that key proteins involved in the presynaptic release mechanism are dysregulated in the disorder. We also discuss the potential impact of dysfunctional presynaptic neurotransmitter release on the various neurotransmitter systems implicated in schizophrenia.
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Affiliation(s)
- Chijioke N Egbujo
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
| | - Duncan Sinclair
- Neuroscience Research Australia, Barker St, Randwick, NSW, 2031, Australia
| | - Chang-Gyu Hahn
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
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32
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Staley LA, Ebbert MTW, Bunker D, Bailey M, Ridge PG, Goate AM, Kauwe JSK. Variants in ACPP are associated with cerebrospinal fluid Prostatic Acid Phosphatase levels. BMC Genomics 2016; 17 Suppl 3:439. [PMID: 27357282 PMCID: PMC4943489 DOI: 10.1186/s12864-016-2787-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Prostatic Acid Phosphatase (PAP) is an enzyme that is produced primarily in the prostate and functions as a cell growth regulator and potential tumor suppressor. Understanding the genetic regulation of this enzyme is important because PAP plays an important role in prostate cancer and is expressed in other tissues such as the brain. METHODS We tested association between 5.8 M SNPs and PAP levels in cerebrospinal fluid across 543 individuals in two datasets using linear regression. We then performed meta-analyses using METAL =with a significance threshold of p < 5 × 10(-8) and removed SNPs where the direction of the effect was different between the two datasets, identifying 289 candidate SNPs that affect PAP cerebrospinal fluid levels. We analyzed each of these SNPs individually and prioritized SNPs that had biologically meaningful functional annotations in wANNOVAR (e.g. non-synonymous, stop gain, 3' UTR, etc.) or had a RegulomeDB score less than 3. RESULTS Thirteen SNPs met our criteria, suggesting they are candidate causal alleles that underlie ACPP regulation and expression. CONCLUSIONS Given PAP's expression in the brain and its role as a cell-growth regulator and tumor suppressor, our results have important implications in brain health such as cancer and other brain diseases including neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) and mental health (e.g., anxiety, depression, and schizophrenia).
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Affiliation(s)
- Lyndsay A Staley
- Department of Biology, Brigham Young University, Provo, UT, 84602, USA
| | - Mark T W Ebbert
- Department of Biology, Brigham Young University, Provo, UT, 84602, USA
| | - Daniel Bunker
- Department of Biology, Brigham Young University, Provo, UT, 84602, USA
| | - Matthew Bailey
- Biology and Biomedical Sciences, Washington University, St. Louis, MO, 63110, USA
| | | | - Perry G Ridge
- Department of Biology, Brigham Young University, Provo, UT, 84602, USA
| | - Alison M Goate
- Department of Neuroscience Icahn School of Medicine, New York, NY, 10029, USA
| | - John S K Kauwe
- Department of Biology, Brigham Young University, Provo, UT, 84602, USA.
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33
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Antonucci F, Corradini I, Fossati G, Tomasoni R, Menna E, Matteoli M. SNAP-25, a Known Presynaptic Protein with Emerging Postsynaptic Functions. Front Synaptic Neurosci 2016; 8:7. [PMID: 27047369 PMCID: PMC4805587 DOI: 10.3389/fnsyn.2016.00007] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 03/07/2016] [Indexed: 12/27/2022] Open
Abstract
A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. The loss or modification of key synaptic proteins directly affects the properties of such networks, ultimately impacting synaptic function. SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis, and, by directly interacting with different calcium channels subunits, it negatively modulates neuronal voltage-gated calcium channels, thus regulating intracellular calcium dynamics. The SNAP-25 gene has been associated with distinct brain diseases, including Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia and bipolar disorder, indicating that the protein may act as a shared biological substrate among different "synaptopathies". The mechanisms by which alterations in SNAP-25 may concur to these psychiatric diseases are still undefined, although alterations in neurotransmitter release have been indicated as potential causative processes. This review summarizes recent work showing that SNAP-25 not only controls exo/endocytic processes at the presynaptic terminal, but also regulates postsynaptic receptor trafficking, spine morphogenesis, and plasticity, thus opening the possibility that SNAP-25 defects may contribute to psychiatric diseases by impacting not only presynaptic but also postsynaptic functions.
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Affiliation(s)
- Flavia Antonucci
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano Milan, Italy
| | - Irene Corradini
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di MilanoMilan, Italy; Istituto di Neuroscienze, Centro Nazionale RicercheMilan, Italy
| | - Giuliana Fossati
- Humanitas Clinical and Research Center, IRCCS Rozzano Rozzano, Italy
| | - Romana Tomasoni
- Humanitas Clinical and Research Center, IRCCS Rozzano Rozzano, Italy
| | - Elisabetta Menna
- Istituto di Neuroscienze, Centro Nazionale RicercheMilan, Italy; Humanitas Clinical and Research Center, IRCCS RozzanoRozzano, Italy
| | - Michela Matteoli
- Istituto di Neuroscienze, Centro Nazionale RicercheMilan, Italy; Humanitas Clinical and Research Center, IRCCS RozzanoRozzano, Italy
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Ching AS, Ahmad-Annuar A. A Perspective on the Role of microRNA-128 Regulation in Mental and Behavioral Disorders. Front Cell Neurosci 2015; 9:465. [PMID: 26696825 PMCID: PMC4677093 DOI: 10.3389/fncel.2015.00465] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 11/16/2015] [Indexed: 12/18/2022] Open
Abstract
MiRNAs are short, non-coding RNA molecules that regulate gene expression post-transcriptionally. Over the past decade, misregulated miRNA pathways have been associated with various diseases such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. In this article, we aim to discuss the role played by miR-128 in neuropsychiatric disorders, and highlight potential target genes from an in silico analysis of predicted miR-128 targets. We also discuss the differences of target gene determination based on a bioinformatics or empirical approach. Using data from TargetScan and published reports, we narrowed the miR-128 target gene list to those that are known to be associated with neuropsychiatric disorders, and found that these genes can be classified into 29 gene clusters and are mostly enriched in cancer and MAPK signaling pathways. We also highlight some recent studies on several of the miR-128 targets which should be investigated further as potential candidate genes for therapeutic interventions.
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Affiliation(s)
- Ai-Sze Ching
- Department of Biomedical Science, Faculty of Medicine, University of Malaya Kuala Lumpur, Malaysia
| | - Azlina Ahmad-Annuar
- Department of Biomedical Science, Faculty of Medicine, University of Malaya Kuala Lumpur, Malaysia
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35
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Thompson PM, Cruz DA, Fucich EA, Olukotun DY, Takahashi M, Itakura M. SNAP-25a/b Isoform Levels in Human Brain Dorsolateral Prefrontal Cortex and Anterior Cingulate Cortex. MOLECULAR NEUROPSYCHIATRY 2015; 1:220-34. [PMID: 27606314 DOI: 10.1159/000441224] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 09/09/2015] [Indexed: 01/03/2023]
Abstract
SNAP-25 is a neurotransmitter vesicular docking protein which has been associated with brain disorders such as attention deficit hyperactivity disorder, bipolar disorder and schizophrenia. In this project, we were interested if clinical factors are associated with differential SNAP-25 expression. We examined the SNAP-25 isoform mRNA and protein levels in postmortem cortex Brodmann's area 9 (BA9) and BA24 (n = 29). Subjects were divided by psychiatric diagnosis, clinical variables including mood state in the last week of life and lifetime impulsiveness. We found affected subjects with a diagnosis of alcohol use disorder (AUD) had a lower level of SNAP-25b BA24 protein compared to those without AUD. Hispanic subjects had lower levels of SNAP-25a, b and BA9 mRNA than Anglo-American subjects. Subjects who smoked had a total pan (total) SNAP-25 BA9/BA24 ratio. Subjects in the group with a low level of anxious-psychotic symptoms had higher SNAP-25a BA24 mRNA compared to normal controls, and both the high and low symptoms groups had higher pan (total) SNAP-25 BA9/BA24 ratios than normal controls. These data expand our understanding of clinical factors associated with SNAP-25. They suggest that SNAP-25 total and isoform levels may be useful biomarkers beyond limited neurological and psychiatric diagnostic categories.
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Affiliation(s)
| | - Dianne A Cruz
- Departments of Psychiatry, University of Texas Health Science Center San Antonio, San Antonio, Tex., USA
| | - Elizabeth A Fucich
- Departments of Pharmacology, University of Texas Health Science Center San Antonio, San Antonio, Tex., USA
| | - Dianna Y Olukotun
- Departments of Psychiatry, University of Texas Health Science Center San Antonio, San Antonio, Tex., USA
| | - Masami Takahashi
- Department of Biochemistry, Kitasato University School of Medicine, Tokyo, Japan
| | - Makoto Itakura
- Department of Biochemistry, Kitasato University School of Medicine, Tokyo, Japan
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36
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Ayhan Y, McFarland R, Pletnikov MV. Animal models of gene-environment interaction in schizophrenia: A dimensional perspective. Prog Neurobiol 2015; 136:1-27. [PMID: 26510407 DOI: 10.1016/j.pneurobio.2015.10.002] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 09/07/2015] [Accepted: 10/22/2015] [Indexed: 12/12/2022]
Abstract
Schizophrenia has long been considered as a disorder with multifactorial origins. Recent discoveries have advanced our understanding of the genetic architecture of the disease. However, even with the increase of identified risk variants, heritability estimates suggest an important contribution of non-genetic factors. Various environmental risk factors have been proposed to play a role in the etiopathogenesis of schizophrenia. These include season of birth, maternal infections, obstetric complications, adverse events at early childhood, and drug abuse. Despite the progress in identification of genetic and environmental risk factors, we still have a limited understanding of the mechanisms whereby gene-environment interactions (G × E) operate in schizophrenia and psychoses at large. In this review we provide a critical analysis of current animal models of G × E relevant to psychotic disorders and propose that dimensional perspective will advance our understanding of the complex mechanisms of these disorders.
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Affiliation(s)
- Yavuz Ayhan
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA; Hacettepe University Faculty of Medicine, Department of Psychiatry, Turkey
| | - Ross McFarland
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, USA
| | - Mikhail V Pletnikov
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA; Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, USA; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, USA.
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37
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Egbujo C, Sinclair D, Borgmann-Winter K, Arnold SE, Turetsky B, Hahn CG. Molecular evidence for decreased synaptic efficacy in the postmortem olfactory bulb of individuals with schizophrenia. Schizophr Res 2015; 168:554-62. [PMID: 26260078 PMCID: PMC5119750 DOI: 10.1016/j.schres.2015.07.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 07/07/2015] [Accepted: 07/10/2015] [Indexed: 10/23/2022]
Abstract
Multiple lines of evidence suggest altered synaptic plasticity/connectivity as a pathophysiologic mechanism for various symptom domains of schizophrenia. Olfactory dysfunction, an endophenotype of schizophrenia, reflects altered activity of the olfactory circuitry, which conveys signals from olfactory receptor neurons to the olfactory cortex via synaptic connections in the glomeruli of the olfactory bulb. The olfactory system begins with intranasal olfactory receptor neuron axons synapsing with mitral and tufted cells in the glomeruli of the olfactory bulb, which then convey signals directly to the olfactory cortex. We hypothesized that olfactory dysfunction in schizophrenia is associated with dysregulation of synaptic efficacy in the glomeruli of the olfactory bulb. To test this, we employed semi-quantitative immunohistochemistry to examine the olfactory bulbs of 13 postmortem samples from schizophrenia and their matched control pairs for glomerular expression of 5 pre- and postsynaptic proteins that are involved in the integrity and function of synapses. In the glomeruli of schizophrenia cases compared to their matched controls, we found significant decreases in three presynaptic proteins which play crucial roles in vesicular glutamate transport - synapsin IIa (-18.05%, p=0.019), synaptophysin (-24.08% p=0.0016) and SNAP-25 (-23.9%, p=0.046). Two postsynaptic proteins important for spine formation and glutamatergic signaling were also decreased-spinophilin (-17.40%, p=0.042) and PSD-95 (-34.06%, p=0.015). These findings provide molecular evidence for decreased efficacy of synapses within the olfactory bulb, which may represent a synaptic mechanism underlying olfactory dysfunction in schizophrenia.
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Affiliation(s)
- Chijioke Egbujo
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - Duncan Sinclair
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - Karin Borgmann-Winter
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA,Children's Hospital of Philadelphia, Philadelphia, PA
| | - Steven E Arnold
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - Bruce Turetsky
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
| | - Chang-Gyu Hahn
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
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Martin MV, Mirnics K, Nisenbaum LK, Vawter MP. Olanzapine Reversed Brain Gene Expression Changes Induced by Phencyclidine Treatment in Non-Human Primates. MOLECULAR NEUROPSYCHIATRY 2015; 1:82-93. [PMID: 26405684 DOI: 10.1159/000430786] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The NMDA receptor antagonist phencyclidine (PCP) creates schizophrenia-like symptoms in normal controls. The effect of PCP on non-human primate brain gene expression was examined and compared to changes induced by olanzapine treatment. Experimental studies of PCP and antipsychotic drugs have direct relevance to understanding the patho-physiology and treatment of schizophrenia. Genome-wide changes in prefrontal cortex gene expression revealed alterations of 146 transcripts in the PCP treatment group compared to vehicle controls. Dysregulated genes were enriched in identified classes implicated in neurological and genetic disorders, including schizophrenia genes from the Psychiatric Genomics Consortium 108 loci as well as cell death in PCP-treated primates. Canonical pathway analysis revealed a significant overrepresentation of several groups including synaptic long-term potentiation and calcium signaling. Olanzapine coadministered with PCP normalized 34% of the 146 PCP-induced probe set expression changes, and a network of 17 olanzapine-normalized genes was identified enriched in schizophrenia candidate genes containing RGS4, SYN1 and AKT as nodes. The results of this study support the use of PCP administration in non-human primates as a glutamatergic model of schizophrenia and suggest that a large number of PCP-induced expression differences can be reversed by olanzapine. The results of this study may be informative for identification of potential candidates for pharmacogenetics and biomarker research related to the treatment of schizophrenia.
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Affiliation(s)
- Maureen V Martin
- Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, Calif
| | - Karoly Mirnics
- Department of Psychiatry, Vanderbilt University, Nashville, Tenn
| | - Laura K Nisenbaum
- Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Ind., USA
| | - Marquis P Vawter
- Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, Calif
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Fossati G, Morini R, Corradini I, Antonucci F, Trepte P, Edry E, Sharma V, Papale A, Pozzi D, Defilippi P, Meier JC, Brambilla R, Turco E, Rosenblum K, Wanker EE, Ziv NE, Menna E, Matteoli M. Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis. Cell Death Differ 2015; 22:1425-36. [PMID: 25678324 DOI: 10.1038/cdd.2014.227] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 10/22/2014] [Accepted: 11/26/2014] [Indexed: 12/24/2022] Open
Abstract
Impairment of synaptic function can lead to neuropsychiatric disorders collectively referred to as synaptopathies. The SNARE protein SNAP-25 is implicated in several brain pathologies and, indeed, brain areas of psychiatric patients often display reduced SNAP-25 expression. It has been recently found that acute downregulation of SNAP-25 in brain slices impairs long-term potentiation; however, the processes through which this occurs are still poorly defined. We show that in vivo acute downregulation of SNAP-25 in CA1 hippocampal region affects spine number. Consistently, hippocampal neurons from SNAP-25 heterozygous mice show reduced densities of dendritic spines and defective PSD-95 dynamics. Finally, we show that, in brain, SNAP-25 is part of a molecular complex including PSD-95 and p140Cap, with p140Cap being capable to bind to both SNAP-25 and PSD-95. These data demonstrate an unexpected role of SNAP-25 in controlling PSD-95 clustering and open the possibility that genetic reductions of the protein levels - as occurring in schizophrenia - may contribute to the pathology through an effect on postsynaptic function and plasticity.
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Affiliation(s)
- G Fossati
- 1] Department of Biotechnology and Translational Medicine, University of Milan, Milano 20129, Italy [2] Humanitas Clinical and Research Center, Laboratory of Pharmacology and Brain Pathology, Via Manzoni 56, Rozzano, 20089 Milano, Italy
| | - R Morini
- 1] Department of Biotechnology and Translational Medicine, University of Milan, Milano 20129, Italy [2] Humanitas Clinical and Research Center, Laboratory of Pharmacology and Brain Pathology, Via Manzoni 56, Rozzano, 20089 Milano, Italy
| | - I Corradini
- 1] Department of Biotechnology and Translational Medicine, University of Milan, Milano 20129, Italy [2] Istituto di Neuroscienze del CNR, Milano 20129, Italy
| | - F Antonucci
- 1] Department of Biotechnology and Translational Medicine, University of Milan, Milano 20129, Italy [2] Istituto di Neuroscienze del CNR, Milano 20129, Italy
| | - P Trepte
- Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Berlin 13125, Germany
| | - E Edry
- Sagol Department of Neurobiology, Center for Gene Manipulation in the Adult Brain (CGMB), Haifa University, Haifa, Israel
| | - V Sharma
- Sagol Department of Neurobiology, Center for Gene Manipulation in the Adult Brain (CGMB), Haifa University, Haifa, Israel
| | - A Papale
- Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute and University, Milano 20132, Italy
| | - D Pozzi
- Humanitas Clinical and Research Center, Laboratory of Pharmacology and Brain Pathology, Via Manzoni 56, Rozzano, 20089 Milano, Italy
| | - P Defilippi
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10124, Italy
| | - J C Meier
- 1] RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany [2] TU Braunschweig, Zoological Institute, Division of Cell Biology and Cell Physiology, Braunschweig, Germany
| | - R Brambilla
- Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute and University, Milano 20132, Italy
| | - E Turco
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10124, Italy
| | - K Rosenblum
- Sagol Department of Neurobiology, Center for Gene Manipulation in the Adult Brain (CGMB), Haifa University, Haifa, Israel
| | - E E Wanker
- Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Berlin 13125, Germany
| | - N E Ziv
- Network Biology Labs and Faculty of Medicine, Technion, 33000 Haifa, Israel
| | - E Menna
- 1] Humanitas Clinical and Research Center, Laboratory of Pharmacology and Brain Pathology, Via Manzoni 56, Rozzano, 20089 Milano, Italy [2] Istituto di Neuroscienze del CNR, Milano 20129, Italy
| | - M Matteoli
- 1] Department of Biotechnology and Translational Medicine, University of Milan, Milano 20129, Italy [2] Humanitas Clinical and Research Center, Laboratory of Pharmacology and Brain Pathology, Via Manzoni 56, Rozzano, 20089 Milano, Italy
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40
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Braida D, Guerini FR, Ponzoni L, Corradini I, De Astis S, Pattini L, Bolognesi E, Benfante R, Fornasari D, Chiappedi M, Ghezzo A, Clerici M, Matteoli M, Sala M. Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies. Transl Psychiatry 2015; 5:e500. [PMID: 25629685 PMCID: PMC4312830 DOI: 10.1038/tp.2014.136] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 11/19/2014] [Indexed: 12/27/2022] Open
Abstract
Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric disorders, including schizophrenia and attention-deficit/hyperactivity disorder. Consistently, SNAP-25 polymorphisms in humans are associated with hyperactivity and/or with low cognitive scores. We analysed five SNAP-25 gene polymorphisms (rs363050, rs363039, rs363043, rs3746544 and rs1051312) in 46 autistic children trying to correlate them with Childhood Autism Rating Scale and electroencephalogram (EEG) abnormalities. The functional effects of rs363050 single-nucleotide polymorphism (SNP) on the gene transcriptional activity, by means of the luciferase reporter gene, were evaluated. To investigate the functional consequences that SNAP-25 reduction may have in children, the behaviour and EEG of SNAP-25(+/-) adolescent mice (SNAP-25(+/+)) were studied. Significant association of SNAP-25 polymorphism with decreasing cognitive scores was observed. Analysis of transcriptional activity revealed that SNP rs363050 encompasses a regulatory element, leading to protein expression decrease. Reduction of SNAP-25 levels in adolescent mice was associated with hyperactivity, cognitive and social impairment and an abnormal EEG, characterized by the occurrence of frequent spikes. Both EEG abnormalities and behavioural deficits were rescued by repeated exposure for 21 days to sodium salt valproate (VLP). A partial recovery of SNAP-25 expression content in SNAP-25(+/-) hippocampi was also observed by means of western blotting. A reduced expression of SNAP-25 is responsible for the cognitive deficits in children affected by autism spectrum disorders, as presumably occurring in the presence of rs363050(G) allele, and for behavioural and EEG alterations in adolescent mice. VLP treatment could result in novel therapeutic strategies.
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Affiliation(s)
- D Braida
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy,Fondazione IRCCS Don Gnocchi, Milan, Italy
| | | | - L Ponzoni
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy,Fondazione Fratelli Confalonieri, Milan, Italy
| | | | - S De Astis
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy
| | - L Pattini
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | | | - R Benfante
- CNR—Neuroscience Institute, Milan, Italy
| | - D Fornasari
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy,CNR—Neuroscience Institute, Milan, Italy
| | - M Chiappedi
- Child Neuropsychiatry Unit, National Neurological Institute C. Mondino, Pavia, Italy
| | - A Ghezzo
- Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy,Associazione Nazionale Famiglie di Persone con Disabilitá Affettiva e/o Relazionale (ANFFAS), Macerata, Italy
| | - M Clerici
- Fondazione IRCCS Don Gnocchi, Milan, Italy,Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy
| | - M Matteoli
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy,Humanitas Clinical and Research Center, Rozzano, Italy
| | - M Sala
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy,CNR—Neuroscience Institute, Milan, Italy,Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli 32, Milan 20129, Italy. E-mail:
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Shen XM, Selcen D, Brengman J, Engel AG. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology 2014; 83:2247-55. [PMID: 25381298 DOI: 10.1212/wnl.0000000000001079] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To identify and characterize the molecular basis of a syndrome associated with myasthenia, cortical hyperexcitability, cerebellar ataxia, and intellectual disability. METHODS We performed in vitro microelectrode studies of neuromuscular transmission, performed exome and Sanger sequencing, and analyzed functional consequences of the identified mutation in expression studies. RESULTS Neuromuscular transmission at patient endplates was compromised by reduced evoked quantal release. Exome sequencing identified a dominant de novo variant, p.Ile67Asn, in SNAP25B, a SNARE protein essential for exocytosis of synaptic vesicles from nerve terminals and of dense-core vesicles from endocrine cells. Ca(2+)-triggered exocytosis is initiated when synaptobrevin attached to synaptic vesicles (v-SNARE) assembles with SNAP25B and syntaxin anchored in the presynaptic membrane (t-SNAREs) into an α-helical coiled-coil held together by hydrophobic interactions. Pathogenicity of the Ile67Asn mutation was confirmed by 2 measures. First, the Ca(2+) triggered fusion of liposomes incorporating v-SNARE with liposomes containing t-SNAREs was hindered when t-SNAREs harbored the mutant SNAP25B moiety. Second, depolarization of bovine chromaffin cells transfected with mutant SNAP25B or with mutant plus wild-type SNAP25B markedly reduced depolarization-evoked exocytosis compared with wild-type transfected cells. CONCLUSION Ile67Asn variant in SNAP25B is pathogenic because it inhibits synaptic vesicle exocytosis. We attribute the deleterious effects of the mutation to disruption of the hydrophobic α-helical coiled-coil structure of the SNARE complex by replacement of a highly hydrophobic isoleucine by a strongly hydrophilic asparagine.
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Affiliation(s)
- Xin-Ming Shen
- From the Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN.
| | - Duygu Selcen
- From the Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN
| | - Joan Brengman
- From the Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN
| | - Andrew G Engel
- From the Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN.
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42
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The role of NMDA receptors in the pathophysiology and treatment of mood disorders. Neurosci Biobehav Rev 2014; 47:336-58. [PMID: 25218759 DOI: 10.1016/j.neubiorev.2014.08.017] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Revised: 08/08/2014] [Accepted: 08/28/2014] [Indexed: 12/31/2022]
Abstract
Mood disorders such as major depressive disorder and bipolar disorder are chronic and recurrent illnesses that cause significant disability and affect approximately 350 million people worldwide. Currently available biogenic amine treatments provide relief for many and yet fail to ameliorate symptoms for others, highlighting the need to diversify the search for new therapeutic strategies. Here we present recent evidence implicating the role of N-methyl-D-aspartate receptor (NMDAR) signaling in the pathophysiology of mood disorders. The possible role of NMDARs in mood disorders has been supported by evidence demonstrating that: (i) both BPD and MDD are characterized by altered levels of central excitatory neurotransmitters; (ii) NMDAR expression, distribution, and function are atypical in patients with mood disorders; (iii) NMDAR modulators show positive therapeutic effects in BPD and MDD patients; and (iv) conventional antidepressants/mood stabilizers can modulate NMDAR function. Taken together, this evidence suggests the NMDAR system holds considerable promise as a therapeutic target for developing next generation drugs that may provide more rapid onset relief of symptoms. Identifying the subcircuits involved in mood and elucidating the role of NMDARs subtypes in specific brain circuits would constitute an important step toward the development of more effective therapies with fewer side effects.
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43
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Mice deficient in transmembrane prostatic acid phosphatase display increased GABAergic transmission and neurological alterations. PLoS One 2014; 9:e97851. [PMID: 24846136 PMCID: PMC4028278 DOI: 10.1371/journal.pone.0097851] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 04/25/2014] [Indexed: 02/06/2023] Open
Abstract
Prostatic acid phosphatase (PAP), the first diagnostic marker and present therapeutic target for prostate cancer, modulates nociception at the dorsal root ganglia (DRG), but its function in the central nervous system has remained unknown. We studied expression and function of TMPAP (the transmembrane isoform of PAP) in the brain by utilizing mice deficient in TMPAP (PAP−/− mice). Here we report that TMPAP is expressed in a subpopulation of cerebral GABAergic neurons, and mice deficient in TMPAP show multiple behavioral and neurochemical features linked to hyperdopaminergic dysregulation and altered GABAergic transmission. In addition to increased anxiety, disturbed prepulse inhibition, increased synthesis of striatal dopamine, and augmented response to amphetamine, PAP-deficient mice have enlarged lateral ventricles, reduced diazepam-induced loss of righting reflex, and increased GABAergic tone in the hippocampus. TMPAP in the mouse brain is localized presynaptically, and colocalized with SNARE-associated protein snapin, a protein involved in synaptic vesicle docking and fusion, and PAP-deficient mice display altered subcellular distribution of snapin. We have previously shown TMPAP to reside in prostatic exosomes and we propose that TMPAP is involved in the control of GABAergic tone in the brain also through exocytosis, and that PAP deficiency produces a distinct neurological phenotype.
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44
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Proteomic Changes in Female Rat Hippocampus Following Exposure to a Terrified Sound Stress. J Mol Neurosci 2014; 53:158-65. [DOI: 10.1007/s12031-014-0242-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 01/15/2014] [Indexed: 12/27/2022]
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45
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Yang J, Hu L, Wu Q, Liu L, Zhao L, Zhao X, Song T, Huang C. A terrified-sound stress induced proteomic changes in adult male rat hippocampus. Physiol Behav 2014; 128:32-8. [PMID: 24518870 DOI: 10.1016/j.physbeh.2014.01.038] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Revised: 01/19/2014] [Accepted: 01/25/2014] [Indexed: 01/24/2023]
Abstract
In this study, we investigated the biochemical mechanisms in the adult rat hippocampus underlying the relationship between a terrified-sound induced psychological stress and spatial learning. Adult male rats were exposed to a terrified-sound stress, and the Morris water maze (MWM) has been used to evaluate changes in spatial learning and memory. The protein expression profile of the hippocampus was examined using two-dimensional gel electrophoresis (2DE), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and bioinformatics analysis. The data from the MWM tests suggested that a terrified-sound stress improved spatial learning. The proteomic analysis revealed that the expression of 52 proteins was down-regulated, while that of 35 proteins were up-regulated, in the hippocampus of the stressed rats. We identified and validated six of the most significant differentially expressed proteins that demonstrated the greatest stress-induced changes. Our study provides the first evidence that a terrified-sound stress improves spatial learning in rats, and that the enhanced spatial learning coincides with changes in protein expression in rat hippocampus.
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Affiliation(s)
- Juan Yang
- Department of Genetics and Molecular Biology, Medical School of Xi'an Jiaotong University, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China
| | - Lili Hu
- Department of Genetics and Molecular Biology, Medical School of Xi'an Jiaotong University, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China
| | - Qiuhua Wu
- Department of Genetics and Molecular Biology, Medical School of Xi'an Jiaotong University, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China
| | - Liying Liu
- Department of Genetics and Molecular Biology, Medical School of Xi'an Jiaotong University, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China
| | - Lingyu Zhao
- Department of Genetics and Molecular Biology, Medical School of Xi'an Jiaotong University, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China
| | - Xiaoge Zhao
- Department of Genetics and Molecular Biology, Medical School of Xi'an Jiaotong University, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China
| | - Tusheng Song
- Department of Genetics and Molecular Biology, Medical School of Xi'an Jiaotong University, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China
| | - Chen Huang
- Department of Genetics and Molecular Biology, Medical School of Xi'an Jiaotong University, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China; Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, 76 Western Yanta Road, Xi'an, Shaanxi 710061, PR China.
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46
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Expression of presynaptic markers in a neurodevelopmental animal model with relevance to schizophrenia. Neuroreport 2013; 24:928-33. [DOI: 10.1097/wnr.0000000000000030] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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47
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Kochlamazashvili G, Haucke V. A dual role of SNAP-25 as carrier and guardian of synaptic transmission. EMBO Rep 2013; 14:579-80. [PMID: 23732543 DOI: 10.1038/embor.2013.74] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
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Kannan G, Sawa A, Pletnikov MV. Mouse models of gene-environment interactions in schizophrenia. Neurobiol Dis 2013; 57:5-11. [PMID: 23748077 DOI: 10.1016/j.nbd.2013.05.012] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 05/10/2013] [Accepted: 05/20/2013] [Indexed: 01/20/2023] Open
Abstract
Gene-environment interactions (GEIs) likely play significant roles in the pathogenesis of schizophrenia and underlie differences in pathological, behavioral, and clinical presentations of the disease. Findings from epidemiology and psychiatric genetics have assisted in the generation of animal models of GEI relevant to schizophrenia. These models may provide a foundation for elucidating the molecular, cellular, and circuitry mechanisms that mediate GEI in schizophrenia. Here we critically review current mouse models of GEI related to schizophrenia, describe directions for their improvement, and propose endophenotypes to provide a more tangible basis for molecular studies of pathways of GEI and facilitate the identification of novel therapeutic targets.
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Affiliation(s)
- Geetha Kannan
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Monti JM, BaHammam AS, Pandi-Perumal SR, Bromundt V, Spence DW, Cardinali DP, Brown GM. Sleep and circadian rhythm dysregulation in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2013; 43:209-16. [PMID: 23318689 DOI: 10.1016/j.pnpbp.2012.12.021] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Revised: 12/04/2012] [Accepted: 12/27/2012] [Indexed: 12/18/2022]
Abstract
Sleep-onset and maintenance insomnia is a common symptom in schizophrenic patients regardless of either their medication status (drug-naive or previously treated) or the phase of the clinical course (acute or chronic). Regarding sleep architecture, the majority of studies indicate that non-rapid eye movement (NREM), N3 sleep and REM sleep onset latency are reduced in schizophrenia, whereas REM sleep duration tends to remain unchanged. Many of these sleep disturbances in schizophrenia appear to be caused by abnormalities of the circadian system as indicated by misalignments of the endogenous circadian cycle and the sleep-wake cycle. Circadian disruption, sleep onset insomnia and difficulties in maintaining sleep in schizophrenic patients could be partly related to a presumed hyperactivity of the dopaminergic system and dysfunction of the GABAergic system, both associated with core features of schizophrenia and with signaling in sleep and wake promoting brain regions. Since multiple neurotransmitter systems within the CNS can be implicated in sleep disturbances in schizophrenia, the characterization of the neurotransmitter systems involved remains a challenging dilemma.
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Affiliation(s)
- Jaime M Monti
- Department of Pharmacology and Therapeutics, Clinics Hospital, Montevideo, 11600, Uruguay
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50
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Ohira K, Kobayashi K, Toyama K, Nakamura HK, Shoji H, Takao K, Takeuchi R, Yamaguchi S, Kataoka M, Otsuka S, Takahashi M, Miyakawa T. Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice. Mol Brain 2013; 6:12. [PMID: 23497716 PMCID: PMC3605216 DOI: 10.1186/1756-6606-6-12] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 02/21/2013] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Synaptosomal-associated protein, 25 kDa (SNAP-25) regulates the exocytosis of neurotransmitters. Growing evidence suggests that SNAP-25 is involved in neuropsychiatric disorders, such as schizophrenia, attention-deficit/hyperactivity disorder, and epilepsy. Recently, increases in anxiety-related behaviors and epilepsy have been observed in SNAP-25 knock-in (KI) mice, which have a single amino acid substitution of Ala for Ser187. However, the molecular and cellular mechanisms underlying the abnormalities in this mutant remain unknown. RESULTS In this study, we found that a significant number of dentate gyrus (DG) granule cells was histologically and electrophysiologically similar to immature DG neurons in the dentate gyrus of the adult mutants, a phenomenon termed the "immature DG" (iDG). SNAP-25 KI mice and other mice possessing the iDG phenotype, i.e., alpha-calcium/calmodulin-dependent protein kinase II heterozygous mice, Schnurri-2 knockout mice, and mice treated with the antidepressant fluoxetine, showed similar molecular expression patterns, with over 100 genes similarly altered. A working memory deficit was also identified in mutant mice during a spontaneous forced alternation task using a modified T-maze, a behavioral task known to be dependent on hippocampal function. Chronic treatments with the antiepileptic drug valproate abolished the iDG phenotype and the working memory deficit in mutants. CONCLUSIONS These findings suggest that the substitution of Ala for Ser187 in SNAP-25 induces the iDG phenotype, which can also be caused by epilepsy, and led to a severe working memory deficit. In addition, the iDG phenotype in adulthood is likely an endophenotype for at least a part of some common psychiatric disorders.
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Affiliation(s)
- Koji Ohira
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, 470-1192, Japan
- Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan
| | - Katsunori Kobayashi
- Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan
- Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, Tokyo, 113-8602, Japan
| | - Keiko Toyama
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, 470-1192, Japan
- Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan
| | - Hironori K Nakamura
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, 470-1192, Japan
- Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan
| | - Hirotaka Shoji
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, 470-1192, Japan
- Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan
| | - Keizo Takao
- Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan
- Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan
| | - Rika Takeuchi
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, 470-1192, Japan
- Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan
| | - Shun Yamaguchi
- Division of Morphological Neuroscience, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
- JST, PRESTO, Kawaguchi, 332-0012, Japan
| | - Masakazu Kataoka
- Department of Environmental Science and Technology, Faculty of Engineering, Shinshu University, Nagano, 380-8553, Japan
| | - Shintaro Otsuka
- Department of Biochemistry, Kitasato University School of Medicine, Sagamihara, 228-8555, Japan
| | - Masami Takahashi
- Department of Biochemistry, Kitasato University School of Medicine, Sagamihara, 228-8555, Japan
| | - Tsuyoshi Miyakawa
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, 470-1192, Japan
- Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, 332-0012, Japan
- Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan
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