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Kim IB, Kim MH, Jung S, Kim WK, Lee J, Ju YS, Webster MJ, Kim S, Kim JH, Kim HJ, Kim J, Kim S, Lee JH. Low-level brain somatic mutations in exonic regions are collectively implicated in autism with germline mutations in autism risk genes. Exp Mol Med 2024; 56:1750-1762. [PMID: 39085355 PMCID: PMC11372092 DOI: 10.1038/s12276-024-01284-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 04/15/2024] [Accepted: 05/12/2024] [Indexed: 08/02/2024] Open
Abstract
Low-level somatic mutations in the human brain are implicated in various neurological disorders. The contribution of low-level brain somatic mutations to autism spectrum disorder (ASD), however, remains poorly understood. Here, we performed high-depth exome sequencing with an average read depth of 559.3x in 181 cortical, cerebellar, and peripheral tissue samples to identify brain somatic single nucleotide variants (SNVs) in 24 ASD subjects and 31 controls. We detected ~2.4 brain somatic SNVs per exome per single brain region, with a variant allele frequency (VAF) as low as 0.3%. The mutational profiles, including the number, signature, and type, were not significantly different between the ASD patients and controls. Intriguingly, when considering genes with low-level brain somatic SNVs and ASD risk genes with damaging germline SNVs together, the merged set of genes carrying either somatic or germline SNVs in ASD patients was significantly involved in ASD-associated pathophysiology, including dendrite spine morphogenesis (p = 0.025), mental retardation (p = 0.012), and intrauterine growth retardation (p = 0.012). Additionally, the merged gene set showed ASD-associated spatiotemporal expression in the early and mid-fetal cortex, striatum, and thalamus (all p < 0.05). Patients with damaging mutations in the merged gene set had a greater ASD risk than did controls (odds ratio = 3.92, p = 0.025, 95% confidence interval = 1.12-14.79). The findings of this study suggest that brain somatic SNVs and germline SNVs may collectively contribute to ASD-associated pathophysiology.
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Affiliation(s)
- Il Bin Kim
- Department of Psychiatry, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, 06135, Republic of Korea
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Myeong-Heui Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Saehoon Jung
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Woo Kyeong Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Junehawk Lee
- Center for Supercomputing Applications, Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon, 34141, Republic of Korea
| | - Young Seok Ju
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Maree J Webster
- Stanley Medical Research Institute, Laboratory of Brain Research, 9800 Medical Center Drive, Suite C-050, Rockville, MD, 20850, USA
| | - Sanghyeon Kim
- Stanley Medical Research Institute, Laboratory of Brain Research, 9800 Medical Center Drive, Suite C-050, Rockville, MD, 20850, USA
| | - Ja Hye Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Hyun Jung Kim
- Department of Anatomy, Korea University College of Medicine, Seoul, 02841, Republic of Korea
| | - Junho Kim
- Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Sangwoo Kim
- Department of Biomedical Systems Informatics and Brain Korea 21 PLUS for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| | - Jeong Ho Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.
- SoVarGen, SoVarGen, Inc., Daejeon, 34141, Republic of Korea.
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Shuang R, Gao T, Sun Z, Tong Y, Zhao K, Wang H. Tet1/DLL3/Notch1 signal pathway affects hippocampal neurogenesis and regulates depression-like behaviour in mice. Eur J Pharmacol 2024; 968:176417. [PMID: 38346470 DOI: 10.1016/j.ejphar.2024.176417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 02/08/2024] [Accepted: 02/09/2024] [Indexed: 02/24/2024]
Abstract
Ten-eleven translocation protein 1 (Tet1) is associated with the regulation of depression-like behaviour in mice. However, the mechanism by which Tet1 affects neurogenesis in mice to regulate depression-like behaviours remains unclear. In this study, the chronic social defeat stress (CSDS) paradigm was constructed by overexpressing Tet1 protein in the mouse hippocampus, and 5-ethynyl-2'-deoxyuridine (EdU, 50 mg/kg) was injected on the seventh day to explore the mechanism of the regulation of the Tet1/Delta-like protein 3 (DLL3)/Notch1 protein pathway in mice hippocampal neurogenesis and its influence on depression-like behaviour. Following CSDS, the expression level of Tet1 decreased significantly. Moreover, due to the downregulation of Tet1 protein, the maintenance of the DNA methylation and demethylation balance was affected, resulting in a significant increase in the methylation levels of Notch1 and DLL3 and a significant decrease in the protein expression levels of DLL3, Notch1, and brain-derived neurotrophic factor (BDNF). At the same time, the proliferation and differentiation of neurones were affected, which was related to a significant decrease in the number of EdU+, doublecortin (DCX)+, and Ki67+ cells in the hippocampus of the CSDS model mice. When the Tet1 protein was overexpressed in the mouse hippocampus, DLL3 and Notch1 protein expression levels were upregulated, promoting hippocampal neurogenesis and alleviating depression-like behaviour in mice. These findings suggest that regulation of the hippocampal Tet1/DLL3/Notch1 protein pathway to influence neurogenesis may be a therapeutic strategy for depression.
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Affiliation(s)
- Ruonan Shuang
- Ningxia Medical University, Yinchuan, Ningxia, 750004, China; Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Tiantian Gao
- Ningxia Medical University, Yinchuan, Ningxia, 750004, China
| | - Zhongwen Sun
- College of Medicine, Lishui University, Lishui, 323000, China
| | - Yue Tong
- Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Keke Zhao
- Ningxia Medical University, Yinchuan, Ningxia, 750004, China
| | - Hanqing Wang
- Ningxia Medical University, Yinchuan, Ningxia, 750004, China.
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Noll JM, Sherafat AA, Ford GD, Ford BD. The case for neuregulin-1 as a clinical treatment for stroke. Front Cell Neurosci 2024; 18:1325630. [PMID: 38638304 PMCID: PMC11024452 DOI: 10.3389/fncel.2024.1325630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 03/01/2024] [Indexed: 04/20/2024] Open
Abstract
Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.
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Affiliation(s)
- Jessica M. Noll
- Division of Biomedical Sciences, University of California-Riverside School of Medicine, Riverside, CA, United States
- Nanostring Technologies, Seattle, WA, United States
| | - Arya A. Sherafat
- Division of Biomedical Sciences, University of California-Riverside School of Medicine, Riverside, CA, United States
| | - Gregory D. Ford
- Southern University-New Orleans, New Orleans, LA, United States
| | - Byron D. Ford
- Department of Anatomy, Howard University College of Medicine, Washington, DC, United States
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4
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Yi Y, Zhang Y, Song Y, Lu Y. Treadmill Running Regulates Adult Neurogenesis, Spatial and Non-spatial Learning, Parvalbumin Neuron Activity by ErbB4 Signaling. Cell Mol Neurobiol 2024; 44:17. [PMID: 38285192 PMCID: PMC11407172 DOI: 10.1007/s10571-023-01439-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 11/06/2023] [Indexed: 01/30/2024]
Abstract
Exercise can promote adult neurogenesis and improve symptoms associated with schizophrenia and other mental disorders via parvalbumin (PV)-positive GABAergic interneurons in the dentate gyrus ErbB4 is the receptor of neurotrophic factor neuregulin 1, expressed mostly in PV-positive interneurons. Whether ErbB4 in PV-positive neurons mediates the beneficial effect of exercise and adult neurogenesis on mental disorder needs to be further investigation. Here, we first conducted a four-week study on the effects of AG1478, an ErbB4 inhibitor, on memory and neurogenesis. AG1478 significantly impaired the performance in several memory tasks, including the T-maze, Morris water maze, and contextual fear conditioning, downregulated the expression of total ErbB4 (T-ErbB4) and the ratio of phosphate-ErbB4 (p-ErbB4) to T-ErbB4, and associated with neurogenesis impairment. Interestingly, AG1478 also appeared to decrease intracellular calcium levels in PV neurons, which could be reversed by exercise. These results suggest exercise may regulate adult neurogenesis and PV neuron activity through ErbB4 signaling. Overall, these findings provide further evidence of the importance of exercise for neurogenesis and suggest that targeting ErbB4 may be a promising strategy for improving memory and other cognitive functions in individuals with mental disorders.
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Affiliation(s)
- Yandong Yi
- Department of Pharmacy, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Department of Physiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuejin Zhang
- Department of Physiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China
- Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuanlong Song
- Department of Physiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China
- Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yisheng Lu
- Department of Physiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
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5
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Lu Z, Zhang M, Lee J, Sziraki A, Anderson S, Zhang Z, Xu Z, Jiang W, Ge S, Nelson PT, Zhou W, Cao J. Tracking cell-type-specific temporal dynamics in human and mouse brains. Cell 2023; 186:4345-4364.e24. [PMID: 37774676 PMCID: PMC10545416 DOI: 10.1016/j.cell.2023.08.042] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 05/28/2023] [Accepted: 08/30/2023] [Indexed: 10/01/2023]
Abstract
Progenitor cells are critical in preserving organismal homeostasis, yet their diversity and dynamics in the aged brain remain underexplored. We introduced TrackerSci, a single-cell genomic method that combines newborn cell labeling and combinatorial indexing to characterize the transcriptome and chromatin landscape of proliferating progenitor cells in vivo. Using TrackerSci, we investigated the dynamics of newborn cells in mouse brains across various ages and in a mouse model of Alzheimer's disease. Our dataset revealed diverse progenitor cell types in the brain and their epigenetic signatures. We further quantified aging-associated shifts in cell-type-specific proliferation and differentiation and deciphered the associated molecular programs. Extending our study to the progenitor cells in the aged human brain, we identified conserved genetic signatures across species and pinpointed region-specific cellular dynamics, such as the reduced oligodendrogenesis in the cerebellum. We anticipate that TrackerSci will be broadly applicable to unveil cell-type-specific temporal dynamics in diverse systems.
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Affiliation(s)
- Ziyu Lu
- Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA; The David Rockefeller Graduate Program in Bioscience, The Rockefeller University, New York, NY, USA
| | - Melissa Zhang
- Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA
| | - Jasper Lee
- Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA
| | - Andras Sziraki
- Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA; The David Rockefeller Graduate Program in Bioscience, The Rockefeller University, New York, NY, USA
| | - Sonya Anderson
- Department of Pathology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
| | - Zehao Zhang
- Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA; The David Rockefeller Graduate Program in Bioscience, The Rockefeller University, New York, NY, USA
| | - Zihan Xu
- Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA; The David Rockefeller Graduate Program in Bioscience, The Rockefeller University, New York, NY, USA
| | - Weirong Jiang
- Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA
| | - Shaoyu Ge
- Department of Neurobiology & Behavior, SUNY at Stony Brook, Stony Brook, NY, USA
| | - Peter T Nelson
- Department of Pathology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
| | - Wei Zhou
- Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA.
| | - Junyue Cao
- Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, USA.
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Ding CY, Ding YT, Ji H, Wang YY, Zhang X, Yin DM. Genetic labeling reveals spatial and cellular expression pattern of neuregulin 1 in mouse brain. Cell Biosci 2023; 13:79. [PMID: 37147705 PMCID: PMC10161477 DOI: 10.1186/s13578-023-01032-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 04/15/2023] [Indexed: 05/07/2023] Open
Abstract
BACKGROUND Where the gene is expressed determines the function of the gene. Neuregulin 1 (Nrg1) encodes a tropic factor and is genetically linked with several neuropsychiatry diseases such as schizophrenia, bipolar disorder and depression. Nrg1 has broad functions ranging from regulating neurodevelopment to neurotransmission in the nervous system. However, the expression pattern of Nrg1 at the cellular and circuit levels in rodent brain is not full addressed. METHODS Here we used CRISPR/Cas9 techniques to generate a knockin mouse line (Nrg1Cre/+) that expresses a P2A-Cre cassette right before the stop codon of Nrg1 gene. Since Cre recombinase and Nrg1 are expressed in the same types of cells in Nrg1Cre/+ mice, the Nrg1 expression pattern can be revealed through the Cre-reporting mice or adeno-associated virus (AAV) that express fluorescent proteins in a Cre-dependent way. Using unbiased stereology and fluorescence imaging, the cellular expression pattern of Nrg1 and axon projections of Nrg1-positive neurons were investigated. RESULTS In the olfactory bulb (OB), Nrg1 is expressed in GABAergic interneurons including periglomerular (PG) and granule cells. In the cerebral cortex, Nrg1 is mainly expressed in the pyramidal neurons of superficial layers that mediate intercortical communications. In the striatum, Nrg1 is highly expressed in the Drd1-positive medium spiny neurons (MSNs) in the shell of nucleus accumbens (NAc) that project to substantia nigra pars reticulata (SNr). In the hippocampus, Nrg1 is mainly expressed in granule neurons in the dentate gyrus and pyramidal neurons in the subiculum. The Nrg1-expressing neurons in the subiculum project to retrosplenial granular cortex (RSG) and mammillary nucleus (MM). Nrg1 is highly expressed in the median eminence (ME) of hypothalamus and Purkinje cells in the cerebellum. CONCLUSIONS Nrg1 is broadly expressed in mouse brain, mainly in neurons, but has unique expression patterns in different brain regions.
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Affiliation(s)
- Chen-Yun Ding
- Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, 200062, China
- Center of Implant Dentistry, School and Hospital of Stomatology, Liaoning Provincial Key Laboratory of Oral Diseases, China Medical University, Shenyang, 110002, China
| | - Yan-Ting Ding
- Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, 200062, China
| | - Haifeng Ji
- Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, 200062, China
- Shanghai Changning Mental Health Center, Affiliated to East China Normal University, Shanghai, 200335, China
| | - Yao-Yi Wang
- Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, 200062, China
| | - Xinwen Zhang
- Center of Implant Dentistry, School and Hospital of Stomatology, Liaoning Provincial Key Laboratory of Oral Diseases, China Medical University, Shenyang, 110002, China.
- Laboratory Animal Centre, China Medical University, Shenyang, 110001, China.
| | - Dong-Min Yin
- Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, 200062, China.
- NYU-ECNU Institute of Brain and Cognitive Science at NYU Shanghai, Shanghai, 200062, China.
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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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Vega-Torres JD, Ontiveros-Angel P, Terrones E, Stuffle EC, Solak S, Tyner E, Oropeza M, dela Peña I, Obenaus A, Ford BD, Figueroa JD. Short-term exposure to an obesogenic diet during adolescence elicits anxiety-related behavior and neuroinflammation: modulatory effects of exogenous neuregulin-1. Transl Psychiatry 2022; 12:83. [PMID: 35220393 PMCID: PMC8882169 DOI: 10.1038/s41398-022-01788-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 12/27/2021] [Accepted: 01/07/2022] [Indexed: 11/21/2022] Open
Abstract
Childhood obesity leads to hippocampal atrophy and altered cognition. However, the molecular mechanisms underlying these impairments are poorly understood. The neurotrophic factor neuregulin-1 (NRG1) and its cognate ErbB4 receptor play critical roles in hippocampal maturation and function. This study aimed to determine whether exogenous NRG1 administration reduces hippocampal abnormalities and neuroinflammation in rats exposed to an obesogenic Western-like diet (WD). Lewis rats were randomly divided into four groups (12 rats/group): (1) control diet+vehicle (CDV); (2) CD + NRG1 (CDN) (daily intraperitoneal injections: 5 μg/kg/day; between postnatal day, PND 21-PND 41); (3) WD + VEH (WDV); (4) WD + NRG1 (WDN). Neurobehavioral assessments were performed at PND 43-49. Brains were harvested for MRI and molecular analyses at PND 49. We found that NRG1 administration reduced hippocampal volume (7%) and attenuated hippocampal-dependent cued fear conditioning in CD rats (56%). NRG1 administration reduced PSD-95 protein expression (30%) and selectively reduced hippocampal cytokine levels (IL-33, GM-CSF, CCL-2, IFN-γ) while significantly impacting microglia morphology (increased span ratio and reduced circularity). WD rats exhibited reduced right hippocampal volume (7%), altered microglia morphology (reduced density and increased lacunarity), and increased levels of cytokines implicated in neuroinflammation (IL-1α, TNF-α, IL-6). Notably, NRG1 synergized with the WD to increase hippocampal ErbB4 phosphorylation and the tumor necrosis alpha converting enzyme (TACE/ADAM17) protein levels. Although the results did not provide sufficient evidence to conclude that exogenous NRG1 administration is beneficial to alleviate obesity-related outcomes in adolescent rats, we identified a potential novel interaction between obesogenic diet exposure and TACE/ADAM17-NRG1-ErbB4 signaling during hippocampal maturation. Our results indicate that supraoptimal ErbB4 activities may contribute to the abnormal hippocampal structure and cognitive vulnerabilities observed in obese individuals.
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Affiliation(s)
- Julio David Vega-Torres
- grid.43582.380000 0000 9852 649XCenter for Health Disparities and Molecular Medicine and Department of Basic Sciences, Physiology Division, Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA USA
| | - Perla Ontiveros-Angel
- grid.43582.380000 0000 9852 649XCenter for Health Disparities and Molecular Medicine and Department of Basic Sciences, Physiology Division, Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA USA
| | - Esmeralda Terrones
- grid.43582.380000 0000 9852 649XCenter for Health Disparities and Molecular Medicine and Department of Basic Sciences, Physiology Division, Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA USA
| | - Erwin C. Stuffle
- grid.43582.380000 0000 9852 649XCenter for Health Disparities and Molecular Medicine and Department of Basic Sciences, Physiology Division, Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA USA
| | - Sara Solak
- grid.43582.380000 0000 9852 649XDepartment of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA USA
| | - Emma Tyner
- grid.43582.380000 0000 9852 649XDepartment of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA USA
| | - Marie Oropeza
- grid.43582.380000 0000 9852 649XDepartment of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA USA
| | - Ike dela Peña
- grid.43582.380000 0000 9852 649XDepartment of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA USA
| | - Andre Obenaus
- grid.266093.80000 0001 0668 7243Department of Pediatrics, University of California-Irvine, Irvine, CA USA
| | - Byron D. Ford
- grid.266097.c0000 0001 2222 1582Division of Biomedical Sciences, University of California-Riverside School of Medicine, Riverside, CA USA
| | - Johnny D. Figueroa
- grid.43582.380000 0000 9852 649XCenter for Health Disparities and Molecular Medicine and Department of Basic Sciences, Physiology Division, Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, CA USA
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Zavvari F, Alivan F, Abdi M, Jahanbazi Jahan-Abad A, Karimzadeh F. Maternal exercise during pregnancy increases neuregulin-1 and ErbB4 expression in the newborn offspring of Wistar rats. SPORT SCIENCES FOR HEALTH 2022. [DOI: 10.1007/s11332-021-00878-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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10
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Bando SY, Bertonha FB, Pimentel-Silva LR, de Oliveira JGM, Carneiro MAD, Oku MHM, Wen HT, Castro LHM, Moreira-Filho CA. Hippocampal CA3 transcriptional modules associated with granule cell alterations and cognitive impairment in refractory mesial temporal lobe epilepsy patients. Sci Rep 2021; 11:10257. [PMID: 33986407 PMCID: PMC8119682 DOI: 10.1038/s41598-021-89802-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 04/30/2021] [Indexed: 01/03/2023] Open
Abstract
In about a third of the patients with epilepsy the seizures are not drug-controlled. The current limitation of the antiepileptic drug therapy derives from an insufficient understanding of epilepsy pathophysiology. In order to overcome this situation, it is necessary to consider epilepsy as a disturbed network of interactions, instead of just looking for changes in single molecular components. Here, we studied CA3 transcriptional signatures and dentate gyrus histopathologic alterations in hippocampal explants surgically obtained from 57 RMTLE patients submitted to corticoamygdalohippocampectomy. By adopting a systems biology approach, integrating clinical, histopathological, and transcriptomic data (weighted gene co-expression network analysis), we were able to identify transcriptional modules highly correlated with age of disease onset, cognitive dysfunctions, and granule cell alterations. The enrichment analysis of transcriptional modules and the functional characterization of the highly connected genes in each trait-correlated module allowed us to unveil the modules’ main biological functions, paving the way for further investigations on their roles in RMTLE pathophysiology. Moreover, we found 15 genes with high gene significance values which have the potential to become novel biomarkers and/or therapeutic targets in RMTLE.
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Affiliation(s)
- Silvia Yumi Bando
- Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, 05403-900, Brazil
| | - Fernanda Bernardi Bertonha
- Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, 05403-900, Brazil
| | - Luciana Ramalho Pimentel-Silva
- Department of Neurology, Faculdade de Ciências Médicas da Universidade Estadual de Campinas, UNICAMP, Campinas, SP, 13083-887, Brazil
| | | | | | - Mariana Hiromi Manoel Oku
- Department of Neurology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, 05403-900, Brazil
| | - Hung-Tzu Wen
- Epilepsy Surgery Group, Hospital das Clínicas da FMUSP, São Paulo, SP, 05403-900, Brazil
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11
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Grieco SF, Qiao X, Johnston KG, Chen L, Nelson RR, Lai C, Holmes TC, Xu X. Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine. Transl Psychiatry 2021; 11:144. [PMID: 33627623 PMCID: PMC7904825 DOI: 10.1038/s41398-021-01255-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/09/2021] [Accepted: 02/01/2021] [Indexed: 01/03/2023] Open
Abstract
Subanesthetic ketamine evokes rapid antidepressant effects in human patients that persist long past ketamine's chemical half-life of ~2 h. Ketamine's sustained antidepressant action may be due to modulation of cortical plasticity. We find that ketamine ameliorates depression-like behavior in the forced swim test in adult mice, and this depends on parvalbumin-expressing (PV) neuron-directed neuregulin-1 (NRG1)/ErbB4 signaling. Ketamine rapidly downregulates NRG1 expression in PV inhibitory neurons in mouse medial prefrontal cortex (mPFC) following a single low-dose ketamine treatment. This NRG1 downregulation in PV neurons co-tracks with the decreases in synaptic inhibition to mPFC excitatory neurons for up to a week. This results from reduced synaptic excitation to PV neurons, and is blocked by exogenous NRG1 as well as by PV targeted ErbB4 receptor knockout. Thus, we conceptualize that ketamine's effects are mediated through rapid and sustained cortical disinhibition via PV-specific NRG1 signaling. Our findings reveal a novel neural plasticity-based mechanism for ketamine's acute and long-lasting antidepressant effects.
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Affiliation(s)
- Steven F. Grieco
- grid.266093.80000 0001 0668 7243Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA 92697-1275 USA
| | - Xin Qiao
- grid.266093.80000 0001 0668 7243Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA 92697-1275 USA
| | - Kevin G. Johnston
- grid.266093.80000 0001 0668 7243Department of Mathematics, University of California, Irvine, CA 92697-3875 USA
| | - Lujia Chen
- grid.266093.80000 0001 0668 7243Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA 92697-1275 USA
| | - Renetta R. Nelson
- grid.266093.80000 0001 0668 7243Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA 92697-1275 USA
| | - Cary Lai
- grid.411377.70000 0001 0790 959XDepartment of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405-7000 USA
| | - Todd C. Holmes
- grid.19006.3e0000 0000 9632 6718Department of Physiology and Biophysics, School of Medicine, Universityof California, Irvine, CA 92697- 4560 USA ,grid.266093.80000 0001 0668 7243The Center for Neural Circuit Mapping, University of California, Irvine, CA 92697 USA
| | - Xiangmin Xu
- Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, 92697-1275, USA. .,The Center for Neural Circuit Mapping, University of California, Irvine, CA, 92697, USA. .,Department of Biomedical Engineering, University of California, Irvine, CA, 92697-2715, USA. .,Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, 92697-4025, USA. .,Department of Computer Science, University of California, Irvine, CA, 92697-3435, USA.
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12
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Yamasaki S, Aso T, Miyata J, Sugihara G, Hazama M, Nemoto K, Yoshihara Y, Matsumoto Y, Okada T, Togashi K, Murai T, Takahashi H, Suwa T. Early and late effects of electroconvulsive therapy associated with different temporal lobe structures. Transl Psychiatry 2020; 10:344. [PMID: 33051437 PMCID: PMC7553938 DOI: 10.1038/s41398-020-01025-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 08/14/2020] [Accepted: 09/03/2020] [Indexed: 12/31/2022] Open
Abstract
Recent studies examining electroconvulsive therapy (ECT) have reported that early sessions can induce rapid antidepressant and antipsychotic effects, and the early termination of ECT was reported to increase the risk of relapse. We hypothesized that different neural mechanisms associated with the therapeutic effects of ECT may be involved in the different responses observed during the early and late periods of ECT treatment. We investigated whether these antidepressant and antipsychotic effects were associated with temporally and spatially different regional gray matter volume (GMV) changes during ECT. Fourteen patients with major depressive disorder, with or without psychotic features, underwent 3-Tesla structural magnetic resonance imaging scans before (time point [Tp] 1), after the fifth or sixth ECT session (Tp2), and after ECT completion (Tp3). We investigated the regions in which GMV changed between Tp1 and Tp2, Tp2 and Tp3, and Tp1 and Tp3 using voxel-based morphometry. In addition, we investigated the association between regional GMV changes and improvement in depressive or psychotic symptoms. GMV increase in the left superior and inferior temporal gyrus during Tp1-Tp2 was associated with improvement in psychotic symptoms (P < 0.025). GMV increase in the left hippocampus was associated with improvement of depressive symptoms in Tp2-Tp3 (P < 0.05). Our findings suggest that different temporal lobe structures are associated with early antipsychotic and late antidepressant effects of ECT.
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Affiliation(s)
- Shimpei Yamasaki
- grid.258799.80000 0004 0372 2033Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshihiko Aso
- grid.258799.80000 0004 0372 2033Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan ,Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan ,grid.258799.80000 0004 0372 2033Human Brain Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Jun Miyata
- Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Genichi Sugihara
- grid.258799.80000 0004 0372 2033Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan ,grid.265073.50000 0001 1014 9130Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masaaki Hazama
- grid.258799.80000 0004 0372 2033Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kiyotaka Nemoto
- grid.20515.330000 0001 2369 4728Department of Psychiatry, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yujiro Yoshihara
- grid.258799.80000 0004 0372 2033Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan ,grid.258799.80000 0004 0372 2033Human Brain Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yukiko Matsumoto
- grid.258799.80000 0004 0372 2033Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomohisa Okada
- grid.258799.80000 0004 0372 2033Human Brain Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kaori Togashi
- grid.258799.80000 0004 0372 2033Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshiya Murai
- grid.258799.80000 0004 0372 2033Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hidehiko Takahashi
- grid.258799.80000 0004 0372 2033Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan ,grid.265073.50000 0001 1014 9130Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Taro Suwa
- Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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13
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O'Leary LA, Davoli MA, Belliveau C, Tanti A, Ma JC, Farmer WT, Turecki G, Murai KK, Mechawar N. Characterization of Vimentin-Immunoreactive Astrocytes in the Human Brain. Front Neuroanat 2020; 14:31. [PMID: 32848635 PMCID: PMC7406576 DOI: 10.3389/fnana.2020.00031] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 05/26/2020] [Indexed: 12/19/2022] Open
Abstract
Astrocytes are commonly identified by their expression of the intermediate filament protein glial fibrillary acidic protein (GFAP). GFAP-immunoreactive (GFAP-IR) astrocytes exhibit regional heterogeneity in density and morphology in the mouse brain as well as morphological diversity in the human cortex. However, regional variations in astrocyte distribution and morphology remain to be assessed comprehensively. This was the overarching objective of this postmortem study, which mainly exploited the immunolabeling of vimentin (VIM), an intermediate filament protein expressed by astrocytes and endothelial cells which presents the advantage of more extensively labeling cell structures. We compared the densities of vimentin-immunoreactive (VIM-IR) and GFAP-IR astrocytes in various brain regions (prefrontal and primary visual cortex, caudate nucleus, mediodorsal thalamus) from male individuals having died suddenly in the absence of neurological or psychiatric conditions. The morphometric properties of VIM-IR in these brain regions were also assessed. We found that VIM-IR astrocytes generally express the canonical astrocytic markers Aldh1L1 and GFAP but that VIM-IR astrocytes are less abundant than GFAP-IR astrocytes in all human brain regions, particularly in the thalamus, where VIM-IR cells were nearly absent. About 20% of all VIM-IR astrocytes presented a twin cell morphology, a phenomenon rarely observed for GFAP-IR astrocytes. Furthermore VIM-IR astrocytes in the striatum were often seen to extend numerous parallel processes which seemed to give rise to large VIM-IR fiber bundles projecting over long distances. Moreover, morphometric analyses revealed that VIM-IR astrocytes were more complex than their mouse counterparts in functionally homologous brain regions, as has been previously reported for GFAP-IR astrocytes. Lastly, the density of GFAP-IR astrocytes in gray and white matter were inversely correlated with vascular density, but for VIM-IR astrocytes this was only the case in gray matter, suggesting that gliovascular interactions may especially influence the regional heterogeneity of GFAP-IR astrocytes. Taken together, these findings reveal special features displayed uniquely by human VIM-IR astrocytes and illustrate that astrocytes display important region- and marker-specific differences in the healthy human brain.
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Affiliation(s)
- Liam Anuj O'Leary
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada.,Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Maria Antonietta Davoli
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada
| | - Claudia Belliveau
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada.,Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Arnaud Tanti
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada
| | - Jie Christopher Ma
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada
| | - William Todd Farmer
- Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Center, Montreal General Hospital, Montreal, QC, Canada
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada.,Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.,Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Keith Kazuo Murai
- Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Center, Montreal General Hospital, Montreal, QC, Canada
| | - Naguib Mechawar
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada.,Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.,Department of Psychiatry, McGill University, Montreal, QC, Canada
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14
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Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer's Disease Mice. Int J Mol Sci 2020; 21:ijms21031133. [PMID: 32046281 PMCID: PMC7037054 DOI: 10.3390/ijms21031133] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 02/04/2020] [Accepted: 02/05/2020] [Indexed: 01/23/2023] Open
Abstract
Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer’s disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis. Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administered an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and applied an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy. Remarkably, we evidenced a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline showed no significant effect upon the progenitor cell number and constitution. We demonstrated that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identified a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.
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15
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Kataria H, Alizadeh A, Karimi-Abdolrezaee S. Neuregulin-1/ErbB network: An emerging modulator of nervous system injury and repair. Prog Neurobiol 2019; 180:101643. [PMID: 31229498 DOI: 10.1016/j.pneurobio.2019.101643] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 06/07/2019] [Accepted: 06/11/2019] [Indexed: 12/20/2022]
Abstract
Neuregulin-1 (Nrg-1) is a member of the Neuregulin family of growth factors with essential roles in the developing and adult nervous system. Six different types of Nrg-1 (Nrg-1 type I-VI) and over 30 isoforms have been discovered; however, their specific roles are not fully determined. Nrg-1 signals through a complex network of protein-tyrosine kinase receptors, ErbB2, ErbB3, ErbB4 and multiple intracellular pathways. Genetic and pharmacological studies of Nrg-1 and ErbB receptors have identified a critical role for Nrg-1/ErbB network in neurodevelopment including neuronal migration, neural differentiation, myelination as well as formation of synapses and neuromuscular junctions. Nrg-1 signaling is best known for its characterized role in development and repair of the peripheral nervous system (PNS) due to its essential role in Schwann cell development, survival and myelination. However, our knowledge of the impact of Nrg-1/ErbB on the central nervous system (CNS) has emerged in recent years. Ongoing efforts have uncovered a multi-faceted role for Nrg-1 in regulating CNS injury and repair processes. In this review, we provide a timely overview of the most recent updates on Nrg-1 signaling and its role in nervous system injury and diseases. We will specifically highlight the emerging role of Nrg-1 in modulating the glial and immune responses and its capacity to foster neuroprotection and remyelination in CNS injury. Nrg-1/ErbB network is a key regulatory pathway in the developing nervous system; therefore, unraveling its role in neuropathology and repair can aid in development of new therapeutic approaches for nervous system injuries and associated disorders.
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Affiliation(s)
- Hardeep Kataria
- Department of Physiology and Pathophysiology, Regenerative Medicine Program, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Arsalan Alizadeh
- Department of Physiology and Pathophysiology, Regenerative Medicine Program, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Soheila Karimi-Abdolrezaee
- Department of Physiology and Pathophysiology, Regenerative Medicine Program, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
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16
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17
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Pankratova S, Klingelhofer J, Dmytriyeva O, Owczarek S, Renziehausen A, Syed N, Porter AE, Dexter DT, Kiryushko D. The S100A4 Protein Signals through the ErbB4 Receptor to Promote Neuronal Survival. Theranostics 2018; 8:3977-3990. [PMID: 30083275 PMCID: PMC6071530 DOI: 10.7150/thno.22274] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 04/10/2018] [Indexed: 12/21/2022] Open
Abstract
Understanding the mechanisms of neurodegeneration is crucial for development of therapies to treat neurological disorders. S100 proteins are extensively expressed in the injured brain but S100's role and signalling in neural cells remain elusive. We recently demonstrated that the S100A4 protein protects neurons in brain injury and designed S100A4-derived peptides mimicking its beneficial effects. Here we show that neuroprotection by S100A4 involves the growth factor family receptor ErbB4 and its ligand Neuregulin 1 (NRG), key regulators of neuronal plasticity and implicated in multiple brain pathologies. The neuroprotective effect of S100A4 depends on ErbB4 expression and the ErbB4 signalling partners ErbB2/Akt, and is reduced by functional blockade of NRG/ErbB4 in cell models of neurodegeneration. We also detect binding of S100A4 with ErbB1 (EGFR) and ErbB3. S100A4-derived peptides interact with, and signal through ErbB, are neuroprotective in primary and immortalized dopaminergic neurons, and do not affect cell proliferation/motility - features which make them promising as potential neuroprotectants. Our data suggest that the S100-ErbB axis may be an important mechanism regulating neuronal survival and plasticity.
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18
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Olaya JC, Heusner CL, Matsumoto M, Sinclair D, Kondo MA, Karl T, Shannon Weickert C. Overexpression of Neuregulin 1 Type III Confers Hippocampal mRNA Alterations and Schizophrenia-Like Behaviors in Mice. Schizophr Bull 2018; 44:865-875. [PMID: 28981869 PMCID: PMC6007747 DOI: 10.1093/schbul/sbx122] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Neuregulin 1 (NRG1) is a schizophrenia candidate gene whose protein product is involved in neuronal migration, survival, and synaptic plasticity via production of specific isoforms. Importantly, NRG1 type III (NRG1 III) mRNA is increased in humans inheriting a schizophrenia risk haplotype for the NRG1 gene (HapICE), and NRG1 protein levels can be elevated in schizophrenia. The nature by which NRG1 type III overexpression results in schizophrenia-like behavior and brain pathology remains unclear, therefore we constructed a transgenic mouse with Nrg1 III overexpression in forebrain neurons (CamKII kinase+). Here, we demonstrate construct validity for this mouse model, as juvenile and adult Nrg1 III transgenic mice exhibit an overexpression of Nrg1 III mRNA and Nrg1 protein in multiple brain regions. Furthermore, Nrg1 III transgenic mice have face validity as they exhibit schizophrenia-relevant behavioral phenotypes including deficits in social preference, impaired fear-associated memory, and reduced prepulse inhibition. Additionally, microarray assay of hippocampal mRNA uncovered transcriptional alterations downstream of Nrg1 III overexpression, including changes in serotonin receptor 2C and angiotensin-converting enzyme. Transgenic mice did not exhibit other schizophrenia-relevant behaviors including hyperactivity, social withdrawal, or an increased vulnerability to the effects of MK-801 malate. Our results indicate that this novel Nrg1 III mouse is valid for modeling potential pathological mechanisms of some schizophrenia-like behaviors, for determining what other neurobiological changes may be downstream of elevated NRG1 III levels and for preclinically testing therapeutic strategies that may be specifically efficacious in patients with the NRG1 (HapICE) risk genotype.
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Affiliation(s)
- Juan C Olaya
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia,School of Psychiatry, University of New South Wales, Sydney, Australia
| | | | | | - Duncan Sinclair
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia,School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Mari A Kondo
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia,School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Tim Karl
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia,School of Medicine, Western Sydney University, Campbelltown, Australia
| | - Cynthia Shannon Weickert
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia,School of Psychiatry, University of New South Wales, Sydney, Australia,To whom correspondence should be addressed; Neuroscience Research Australia, Barker Street, Randwick, NSW 2031, Australia; tel: +61-2-9399-1117, fax: +61-2-9399-1005, e-mail:
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19
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Wang Y, Zhang Y, Lu Q, Wang Y, Sun X, Zhang S. NRG-1 Stimulates Serum DJ-1 Increase in Breast Cancers. Pathol Oncol Res 2017; 25:71-79. [PMID: 28963699 DOI: 10.1007/s12253-017-0326-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 09/21/2017] [Indexed: 11/29/2022]
Abstract
To explore the relationship between the expression of DJ-1/HER3 and tumor grade in breast cancer, and investigate the effect of HER3 on NRG-1-mediated serum DJ-1 level in vivo. We analyze the expression level of DJ-1 and HER3 in 68 patients with different grades of breast cancer by immunostaining the tissue microarray. Besides, we investigated the serum DJ-1 level by ELISA. We found that the detectable DJ-1 protein expression is decreased, and the HER3 expression is increased in tumor tissue with the progression of breast cancer. There is a significant rise of DJ-1 in serum in vivo with the stimulation of NRG-1. Meanwhile, we found that HER3 knockdown abolishes NRG-1-induced serum DJ-1 increase and HER3 overexpress improves NRG-1-induced serum DJ-1 increase. This study provides a serum biomarker for breast cancer. The results showed that DJ-1 was associated with clinical stage of breast cancer, and NRG-1 increased the dissociation of HER3 and DJ-1, with promoting the level of DJ-1 in peripheral blood. It is suggested that the level of DJ-1 in peripheral blood may be conducive to assess the prognosis of patients with breast cancer and serum DJ-1 levels can serve as an indicator of therapeutic effectiveness for the development of HER3 targeting breast cancer antibody therapies.
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Affiliation(s)
- Yuandong Wang
- Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Yan Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430022, China
| | - Qian Lu
- Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Yiming Wang
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, Sydney, NSW, 2052, Australia
| | - Xinchen Sun
- Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Shu Zhang
- Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China. .,Department of Radiotherapy, Clinical Research Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
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20
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Pino A, Fumagalli G, Bifari F, Decimo I. New neurons in adult brain: distribution, molecular mechanisms and therapies. Biochem Pharmacol 2017; 141:4-22. [PMID: 28690140 DOI: 10.1016/j.bcp.2017.07.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 07/05/2017] [Indexed: 12/16/2022]
Abstract
"Are new neurons added in the adult mammalian brain?" "Do neural stem cells activate following CNS diseases?" "How can we modulate their activation to promote recovery?" Recent findings in the field provide novel insights for addressing these questions from a new perspective. In this review, we will summarize the current knowledge about adult neurogenesis and neural stem cell niches in healthy and pathological conditions. We will first overview the milestones that have led to the discovery of the classical ventricular and hippocampal neural stem cell niches. In adult brain, new neurons originate from proliferating neural precursors located in the subventricular zone of the lateral ventricles and in the subgranular zone of the hippocampus. However, recent findings suggest that new neuronal cells can be added to the adult brain by direct differentiation (e.g., without cell proliferation) from either quiescent neural precursors or non-neuronal cells undergoing conversion or reprogramming to neuronal fate. Accordingly, in this review we will also address critical aspects of the newly described mechanisms of quiescence and direct conversion as well as the more canonical activation of the neurogenic niches and neuroblast reservoirs in pathological conditions. Finally, we will outline the critical elements involved in neural progenitor proliferation, neuroblast migration and differentiation and discuss their potential as targets for the development of novel therapeutic drugs for neurodegenerative diseases.
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Affiliation(s)
- Annachiara Pino
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Italy
| | - Guido Fumagalli
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Italy
| | - Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Italy.
| | - Ilaria Decimo
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Italy.
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21
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Disrupted hippocampal neuregulin-1/ErbB3 signaling and dentate gyrus granule cell alterations in suicide. Transl Psychiatry 2017; 7:e1161. [PMID: 28675388 PMCID: PMC5538115 DOI: 10.1038/tp.2017.132] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 04/28/2017] [Accepted: 05/04/2017] [Indexed: 12/29/2022] Open
Abstract
Neuregulin-1 (NRG1) and ErbB receptors have been associated with psychopathology, and NRG1-ErbB3 signaling has been shown to increase hippocampal neurogenesis and induce antidepressant-like effects. In this study, we aimed to determine whether deficits in NRG1 or ErbBs might be present in the hippocampus of suicide completers. In well-characterized postmortem hippocampal samples from suicides and matched sudden-death controls, we assessed gene expression and methylation using qRT-PCR and EpiTYPER, respectively. Moreover, in hippocampal tissues stained with cresyl violet, stereology was used to quantify numbers of granule cells and of glia. Granule cell body size was examined with a nucleator probe, and granule cell layer volume with a Cavalieri probe. Unmedicated suicides showed sharply decreased hippocampal ErbB3 expression and decreased numbers of ErbB3-expressing granule cell neurons in the anterior dentate gyrus; a phenomenon seemingly reversed by antidepressant treatment. Furthermore, we found ErbB3 expression to be significantly decreased in the dentate gyrus of adult mice exposed to chronic social defeat stress. Taken together, these results reveal novel suicidal endophenotypes in the hippocampus, as well as a putative etiological mechanism underlying suicidality, and suggest that antidepressant or NRG1 treatment may reverse a potential deficit in anterior dentate gyrus granule cell neurons in individuals at risk of dying by suicide.
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22
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Dang R, Guo Y, Zhang L, Chen L, Yang R, Jiang P. Chronic stress and excessive glucocorticoid exposure both lead to altered Neuregulin-1/ErbB signaling in rat myocardium. Steroids 2016; 112:47-53. [PMID: 27133902 DOI: 10.1016/j.steroids.2016.04.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/21/2016] [Accepted: 04/22/2016] [Indexed: 11/20/2022]
Abstract
Exposure to chronic stress or excess glucocorticoids is associated with the development of depression and heart disease, but the underlying mechanisms remain equivocal. While recent evidence has indicated that Neuregulin-1 (NRG1) and its ErbB receptors play an essential role in cardiac function, much is still unknown concerning the biological link between NRG1/ErbB pathway and the stress-induced comorbidity of depression and cardiac dysfunction. Therefore, we examined the protein expression of NRG1 and ErbB receptors in the myocardium of rats following chronic unpredictable mild stress (CUMS) or rats treated with two different doses (0.2 and 2mg/kg/day, respectively) of dexamethasone (Dex). The stressed rats showed elevated expression of NRG1 and phosphorylated ErbB4 (pErbB4) in the myocardium, whereas ErbB2 and pErbB2 were inhibited. The lower dose of Dex enhanced myocardial NRG1/ErbB signaling, but as the dose is increased, while ErbB4 remained activated, the expression of ErbB2 and pErbB2 became compromised. Both CUMS and 2mg/kg of Dex suppressed the downstream Akt and ERK phosphorylation. Although the lower dose of Dex increased myocardial antiapoptotic Bcl-xl expression, a significant decrease of Bcl-xl expression was found in rats treated with the higher dose. Meanwhile, both CUMS and two different doses of Dex induced proapoptotic Bax level. Combined, our data firstly showed (mal)adaptive responses of NRG1/ErbB system in the stressed heart, indicating the potential involvement of NRG1/ErbB pathway in the stress-induced cardiac dysfunction.
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Affiliation(s)
- Ruili Dang
- Institute of Clinical Pharmacy & Pharmacology, Jining First People's Hospital, Jining Medical University, Jining 272000, China
| | - Yujin Guo
- Institute of Clinical Pharmacy & Pharmacology, Jining First People's Hospital, Jining Medical University, Jining 272000, China
| | - Ling Zhang
- Institute of Clinical Pharmacy & Pharmacology, Jining First People's Hospital, Jining Medical University, Jining 272000, China
| | - Lei Chen
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha 410010, China
| | - Ranyao Yang
- Institute of Clinical Pharmacy & Pharmacology, Jining First People's Hospital, Jining Medical University, Jining 272000, China
| | - Pei Jiang
- Institute of Clinical Pharmacy & Pharmacology, Jining First People's Hospital, Jining Medical University, Jining 272000, China.
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Effects of neuregulin-1 administration on neurogenesis in the adult mouse hippocampus, and characterization of immature neurons along the septotemporal axis. Sci Rep 2016; 6:30467. [PMID: 27469430 PMCID: PMC4965755 DOI: 10.1038/srep30467] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Accepted: 07/04/2016] [Indexed: 12/11/2022] Open
Abstract
Adult hippocampal neurogenesis is associated with learning and affective behavioural regulation. Its diverse functionality is segregated along the septotemporal axis from the dorsal to ventral hippocampus. However, features distinguishing immature neurons in these regions have yet to be characterized. Additionally, although we have shown that administration of the neurotrophic factor neuregulin-1 (NRG1) selectively increases proliferation and overall neurogenesis in the mouse ventral dentate gyrus (DG), likely through ErbB3, NRG1's effects on intermediate neurogenic stages in immature neurons are unknown. We examined whether NRG1 administration increases DG ErbB3 phosphorylation. We labeled adultborn cells using BrdU, then administered NRG1 to examine in vivo neurogenic effects on immature neurons with respect to cell survival, morphology, and synaptogenesis. We also characterized features of immature neurons along the septotemporal axis. We found that neurogenic effects of NRG1 are temporally and subregionally specific to proliferation in the ventral DG. Particular morphological features differentiate immature neurons in the dorsal and ventral DG, and cytogenesis differed between these regions. Finally, we identified synaptic heterogeneity surrounding the granule cell layer. These results indicate neurogenic involvement of NRG1-induced antidepressant-like behaviour is particularly associated with increased ventral DG cell proliferation, and identify novel distinctions between dorsal and ventral hippocampal neurogenic development.
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Aging affects new cell production in the adult hippocampus: A quantitative anatomic review. J Chem Neuroanat 2015; 76:64-72. [PMID: 26686289 DOI: 10.1016/j.jchemneu.2015.10.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/08/2015] [Accepted: 10/19/2015] [Indexed: 02/08/2023]
Abstract
In the last century, cognitive impairment in elderly people was considered as the consequence of neuronal death. However, later analyses indicated that age-related reduction in neuron number was limited to specific regions of the central nervous system, and was irrelevant to brain dysfunction in both humans and non-human animals. Recent studies have indicated that progressive diminution of neural plasticity across an individual's life span may underlie age-related brain dysfunction. To date, various factors have been shown to contribute to neural plasticity. In particular, substantial data supports the importance of production of new cells in the adult brain: the rate of hippocampal neurogenesis wanes radically during aging; similarly, white matter homeostasis via oligodendrogenesis is also affected by aging. This review briefly summarizes quantitative studies on adult hippocampal neurogenesis and oligodendrogenesis. Although the hippocampus is traditionally recognized as the memory center of the brain, it has started to emerge as an integrator of cognition and emotion. One of the current research highlights is that diverse functions of the hippocampus are topographically embedded along its longitudinal and transverse axes. Here we discuss alterations in adult neurogenesis and oligodendrogenesis during aging from a topographic view point. The quantitative anatomic approach to age-related alterations in production of new cells in the hippocampus may give a novel insight into how brain functions suffer from aging.
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Yang W, Liu TT, Song XB, Zhang Y, Li ZH, Hao Q, Cui ZH, Liu HL, Lei CL, Liu J. Neuregulin-1 protects against acute optic nerve injury in rat model. J Neurol Sci 2015; 357:157-66. [PMID: 26235969 DOI: 10.1016/j.jns.2015.07.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 06/09/2015] [Accepted: 07/14/2015] [Indexed: 01/23/2023]
Abstract
OBJECTIVES In this study, we employed a rat model and examined the expression pattern of neuregulin-1 (NRG-1) in optic nerve and retinal ganglion cells (RGCs) in response to optic nerve injury to understand the role of NRG-1 in conferring protection against acute optic nerve injury. METHOD Forty-eight male rats were randomly divided into two groups, the sham-operation group (n=24) and optic nerve injury group (n=24). Flash visual evoked potentials (FVEP) and fundography images were acquired at different time points following optic nerve injury (2h, 1d, 2d, 7d, 14d and 28d). Semi-quantitative analysis of NGR-1 expression pattern was performed by immunohistochemistry (IHC) staining. In a related experiment, 100 male rats were randomly divided into NGR-1 treatment group (n=60) (treated with increasing dose of NGR-1 at 0.5μg, 1μg and 3μg), normal saline (NS) group (n=20) and negative control group (n=20). Optic nerve injury was induced in all the animals and in situ cell death was measured by detecting the apoptosis rates using TUNEL assay. RESULTS Fundus photography results revealed no detectable differences between the sham-operation group and optic nerve injury group at 2h, 1d, 2d and 7d. However at 2weeks, the optic discs turned pale in all animals in the optic nerve injury group. NRG-1 expression increased significantly at all time points in the optic nerve injury group (P<0.05), compared to the sham-operation group, with NRG-1 expression peaking at 14d and gradually declining by 28d. Statistically significant differences in amplitude and latency of P100 wave were also detected between the optic nerve injury and sham-operation group (P<0.05). In related experiment, compared to NS group, treatment with 1μg and 3μg of recombinant human NRG-1 resulted in statistically significant FVEP-P100 amplitude values (all P<0.05). Further, compared to the NS group, ganglion cell apoptosis was dramatically reduced in the NRG-1 group at all time points and the reduction was statistically significant in 3μg NRG-1 treatment group at 7d, 14d and 28d (all P<0.05). CONCLUSION Our results strongly suggest that NRG-1 is highly effective in preserving normal optic nerve function and is essential for tissue repair following optic nerve injury. Thus, NRG-1 expression confers protection against acute optic nerve injury in a dose-dependent manner.
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Affiliation(s)
- Wei Yang
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun 130021, PR China
| | - Tao-Tao Liu
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun 130021, PR China
| | - Xiao-Bin Song
- Department of Emergency Surgery, Jilin Province People's Hospital, Changchun 130021, PR China
| | - Yan Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Hospital of Jilin University, Changchun 130021, PR China
| | - Zhao-Hui Li
- Department of Ophthalmology, People's Hospital of Changchun City, Changchun 130021, PR China
| | - Qian Hao
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun 130021, PR China.
| | - Zhi-Hua Cui
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun 130021, PR China.
| | - Hong Lei Liu
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun 130021, PR China
| | - Chun Ling Lei
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun 130021, PR China
| | - Jun Liu
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun 130021, PR China
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Maheu ME, Devorak J, Freibauer A, Davoli MA, Turecki G, Mechawar N. Increased doublecortin (DCX) expression and incidence of DCX-immunoreactive multipolar cells in the subventricular zone-olfactory bulb system of suicides. Front Neuroanat 2015; 9:74. [PMID: 26082689 PMCID: PMC4450175 DOI: 10.3389/fnana.2015.00074] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 05/17/2015] [Indexed: 01/18/2023] Open
Abstract
Postmortem studies have confirmed the occurrence of adult hippocampal neurogenesis in humans and implicated this process in antidepressant response, yet neurogenesis in other regions remains to be examined in the context of depression. Here we assess the extent of subventricular zone-olfactory bulb (SVZ-OB) neurogenesis in adult humans having died by suicide. Protein expression of proliferative and neurogenic markers Sox2, proliferating cell nuclear antigen, and doublecortin (DCX) were examined in postmortem SVZ and OB samples from depressed suicides and matched sudden-death controls. In the SVZ, DCX-immunoreactive (IR) cells displayed phenotypes typical of progenitors, whereas in the olfactory tract (OT), they were multipolar with variable size and morphologies suggestive of differentiating cells. DCX expression was significantly increased in the OB of suicides, whereas SVZ DCX expression was higher among unmedicated, but not antidepressant-treated, suicides. Although very few DCX-IR cells were present in the control OT, they were considerably more common in suicides and correlated with OB DCX levels. Suicides also displayed higher DCX-IR process volumes. These results support the notion that OB neurogenesis is minimal in adult humans. They further raise the possibility that the differentiation and migration of SVZ-derived neuroblasts may be altered in unmedicated suicides, leading to an accumulation of ectopically differentiating cells in the OT. Normal SVZ DCX expression among suicides receiving antidepressants suggests a potentially novel mode of action of antidepressant medication. Given the modest group sizes and rarity of DCX-IR cells assessed here, a larger-scale characterization will be required before firm conclusions can be made regarding the identity of these cells.
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Affiliation(s)
- Marissa E Maheu
- McGill Group for Suicide Studies, Douglas Mental Health University Institute Montreal, QC, Canada ; Integrated Program in Neuroscience, McGill University Montreal, QC, Canada
| | - Julia Devorak
- McGill Group for Suicide Studies, Douglas Mental Health University Institute Montreal, QC, Canada
| | - Alexander Freibauer
- McGill Group for Suicide Studies, Douglas Mental Health University Institute Montreal, QC, Canada
| | - Maria Antonietta Davoli
- McGill Group for Suicide Studies, Douglas Mental Health University Institute Montreal, QC, Canada
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute Montreal, QC, Canada ; Integrated Program in Neuroscience, McGill University Montreal, QC, Canada ; Department of Psychiatry, McGill University Montreal, QC, Canada
| | - Naguib Mechawar
- McGill Group for Suicide Studies, Douglas Mental Health University Institute Montreal, QC, Canada ; Integrated Program in Neuroscience, McGill University Montreal, QC, Canada ; Department of Psychiatry, McGill University Montreal, QC, Canada
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27
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Egeland M, Zunszain PA, Pariante CM. Molecular mechanisms in the regulation of adult neurogenesis during stress. Nat Rev Neurosci 2015; 16:189-200. [PMID: 25790864 DOI: 10.1038/nrn3855] [Citation(s) in RCA: 141] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Coping with stress is fundamental for mental health, but understanding of the molecular neurobiology of stress is still in its infancy. Adult neurogenesis is well known to be regulated by stress, and conversely adult neurogenesis regulates stress responses. Recent studies in neurogenic cells indicate that molecular pathways activated by glucocorticoids, the main stress hormones, are modulated by crosstalk with other stress-relevant mechanisms, including inflammatory mediators, neurotrophic factors and morphogen signalling pathways. This Review discusses the pathways that are involved in this crosstalk and thus regulate this complex relationship between adult neurogenesis and stress.
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Affiliation(s)
- Martin Egeland
- Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Patricia A Zunszain
- Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Carmine M Pariante
- Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 125 Coldharbour Lane, London, SE5 9NU, UK
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28
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Biernacka JM, Sangkuhl K, Jenkins G, Whaley RM, Barman P, Batzler A, Altman RB, Arolt V, Brockmöller J, Chen CH, Domschke K, Hall-Flavin DK, Hong CJ, Illi A, Ji Y, Kampman O, Kinoshita T, Leinonen E, Liou YJ, Mushiroda T, Nonen S, Skime MK, Wang L, Baune BT, Kato M, Liu YL, Praphanphoj V, Stingl JC, Tsai SJ, Kubo M, Klein TE, Weinshilboum R. The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response. Transl Psychiatry 2015; 5:e553. [PMID: 25897834 PMCID: PMC4462610 DOI: 10.1038/tp.2015.47] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 03/01/2015] [Indexed: 12/21/2022] Open
Abstract
Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. The top association result in the meta-analysis of response represents SNPs 5′ upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.
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Affiliation(s)
- J M Biernacka
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA,Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA,Department of Psychiatry and Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail:
| | - K Sangkuhl
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - G Jenkins
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - R M Whaley
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - P Barman
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - A Batzler
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - R B Altman
- Department of Genetics, Stanford University, Stanford, CA, USA,Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - V Arolt
- Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany
| | - J Brockmöller
- Department of Clinical Pharmacology, University Göttingen, Göttingen, Germany
| | - C H Chen
- Department of Psychiatry, Taipei Medical University-Shuangho Hospital, New Taipei City, Taiwan
| | - K Domschke
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany
| | - D K Hall-Flavin
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
| | - C J Hong
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan,Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - A Illi
- Department of Psychiatry, School of Medicine, University of Tampere, Tampere, Finland
| | - Y Ji
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - O Kampman
- Department of Psychiatry, School of Medicine, University of Tampere, Tampere, Finland,Department of Psychiatry, Seinäjoki Hospital District, Seinäjoki, Finland
| | - T Kinoshita
- Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan
| | - E Leinonen
- Department of Psychiatry, School of Medicine, University of Tampere, Tampere, Finland,Department of Psychiatry, Tampere University Hospital, Tampere, Finland
| | - Y J Liou
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan,Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - T Mushiroda
- RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - S Nonen
- Department of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan
| | - M K Skime
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
| | - L Wang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - B T Baune
- Department of Psychiatry, University of Adelaide, Adelaide, SA, Australia
| | - M Kato
- Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan
| | - Y L Liu
- Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan
| | - V Praphanphoj
- Center for Medical Genetics Research, Rajanukul Institute, Department of Mental Health, Ministry of Public Health Bangkok, Bangkok, Thailand
| | - J C Stingl
- Research Division Federal Institute for Drugs and Medical Devices, Bonn, Germany
| | - S J Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan,Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - M Kubo
- RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - T E Klein
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - R Weinshilboum
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
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Engel M, Snikeris P, Jenner A, Karl T, Huang XF, Frank E. Neuregulin 1 Prevents Phencyclidine-Induced Behavioral Impairments and Disruptions to GABAergic Signaling in Mice. Int J Neuropsychopharmacol 2015; 18:pyu114. [PMID: 26478928 PMCID: PMC4540095 DOI: 10.1093/ijnp/pyu114] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Substantial evidence from human post-mortem and genetic studies has linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic animal models and in vitro experiments have suggested that altered NRG1 signaling, rather than protein changes, contributes to the symptomatology of schizophrenia. However, little is known about the effect of NRG1 on schizophrenia-relevant behavior and neurotransmission (particularly GABAergic and glutamatergic) in adult animals. METHOD To address this question, we treated adult mice with the extracellular signaling domain of NRG1 and assessed spontaneous locomotor activity and acoustic startle response, as well as extracellular GABA, glutamate, and glycine levels in the prefrontal cortex and hippocampus via microdialysis. Furthermore, we asked whether the effect of NRG1 would differ under schizophrenia-relevant impairments in mice and therefore co-treated mice with NRG1 and phencyclidine (PCP) (3 mg/kg). RESULTS Acute intraventricularly- or systemically-injected NRG1 did not affect spontaneous behavior, but prevented PCP induced hyperlocomotion and deficits of prepulse inhibition. NRG1 retrodialysis (10 nM) reduced extracellular glutamate and glycine levels in the prefrontal cortex and hippocampus, and prevented PCP-induced increase in extracellular GABA levels in the hippocampus. CONCLUSION With these results, we provide the first compelling in vivo evidence for the involvement of NRG1 signaling in schizophrenia-relevant behavior and neurotransmission in the adult nervous system, which highlight its treatment potential. Furthermore, the ability of NRG1 treatment to alter GABA, glutamate, and glycine levels in the presence of PCP also suggests that NRG1 signaling has the potential to alter disrupted neurotransmission in patients with schizophrenia.
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Depboylu C, Rösler TW, de Andrade A, Oertel WH, Höglinger GU. Systemically administered neuregulin-1β1 rescues nigral dopaminergic neurons via the ErbB4 receptor tyrosine kinase in MPTP mouse models of Parkinson's disease. J Neurochem 2015; 133:590-7. [PMID: 25581060 DOI: 10.1111/jnc.13026] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 12/24/2014] [Accepted: 12/29/2014] [Indexed: 12/16/2022]
Abstract
Previously, we demonstrated that systemically injected extracellular domain of neuregulin-1β1 (Nrg1β1), a nerve growth and differentiation factor, passes the blood-brain barrier and rescues dopaminergic neurons of substantia nigra in the 6-hydroxydopamine-mouse model of Parkinson's disease (PD). Here, we studied the effects of peripherally administered Nrg1β1 in another toxin-based mouse model of PD. For this purpose, (i) nigrostriatal pathway injury was induced by treatment of adult wild-type mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in acute and subchronic paradigms; and (ii) Nrg1β1 or saline (control) were administered 1 h before each MPTP injection. We found that Nrg1β1 significantly reduced the loss of nigral dopaminergic neurons in both intoxication paradigms (7 days post-injection). However, Nrg1β1 did not reverse MPTP-induced decrease in dopamine levels and dopaminergic fibers in the striatum. We also show that MPTP conversion to its toxic metabolite 1-methyl-4-phenylpyridinium as well as levels of dopamine transporter, mediating intracellular uptake of 1-methyl-4-phenylpyridinium, are unaffected by Nrg1β1. Finally, neuroprotective properties of Nrg1β1 on nigral dopaminergic neurons are specifically mediated by ErbB4 as revealed through the study of ErbB4 knockout mice. In conclusion, systemically administered Nrg1β1 protects midbrain dopaminergic neurons against this PD-related toxic insult. Thus, Nrg1β1 may have a benefit in the treatment of PD patients. Previously, we demonstrated that systemically administered neuregulin-1β1 (Nrg1β1) passes the blood-brain barrier, phosphorylates ErbB4 receptors and elevates dopamine (DA) levels in the nigrostriatal system of healthy mice. Nrg1β1 protects nigral DAergic neurons in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD). Here, we show that Nrg1β1 rescues nigral DAergic neurons also against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced cell death. ErbB4 expression is essential for the neuroprotective effect of Nrg1β1 on midbrain DAergic neurons. Nrg1β1 might be beneficial in PD treatment.
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Affiliation(s)
- Candan Depboylu
- Department of Neurology, Philipps University, Marburg, Germany
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Wakuda T, Iwata K, Iwata Y, Anitha A, Takahashi T, Yamada K, Vasu MM, Matsuzaki H, Suzuki K, Mori N. Perinatal asphyxia alters neuregulin-1 and COMT gene expression in the medial prefrontal cortex in rats. Prog Neuropsychopharmacol Biol Psychiatry 2015; 56:149-54. [PMID: 25194460 DOI: 10.1016/j.pnpbp.2014.08.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 08/04/2014] [Accepted: 08/04/2014] [Indexed: 02/07/2023]
Abstract
Epidemiological studies suggest that perinatal complications, particularly hypoxia-related ones, increase the risk of schizophrenia. Recent genetic studies of the disorder have identified several putative susceptibility genes, some of which are known to be regulated by hypoxia. It can be postulated therefore that birth complications that cause hypoxia in the fetal brain may be associated with a dysregulation in the expression of some of the schizophrenia candidate genes. To test this, we used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Caesarean section birth, and examined the expression of mRNA of five of the putative susceptibility genes (NRG1, ErbB4, AKT1, COMT and BDNF) by real-time quantitative PCR in the medial prefrontal cortex (mPFC) and the hippocampus at 6 and 12 weeks after birth. The expression of NRG1 mRNA was significantly decreased in the mPFC, but not in the hippocampus, at 6 and 12 weeks after birth. In addition, a significant increase in COMT mRNA expression was observed in the mPFC at 12 weeks. The alteration in mRNA levels of NRG1 and COMT was not associated with a change in their protein levels. These results suggest that perinatal asphyxia may lead to disturbances in the PFC, which in turn may exert a long-lasting influence on the expression of specific genes, such as NRG1 and COMT. Our results also suggest that translational interruption may occur in this model of perinatal asphyxia.
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Affiliation(s)
- Tomoyasu Wakuda
- Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Keiko Iwata
- Research Center for Child Mental Development, University of Fukui, Eiheiji-cho, Japan
| | - Yasuhide Iwata
- Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Ayyappan Anitha
- Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Taro Takahashi
- Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Kohei Yamada
- Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Mahesh Mundalil Vasu
- Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Hideo Matsuzaki
- Research Center for Child Mental Development, University of Fukui, Eiheiji-cho, Japan
| | - Katsuaki Suzuki
- Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
| | - Norio Mori
- Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan
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O'Leary OF, Cryan JF. A ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis. Trends Pharmacol Sci 2014; 35:675-87. [PMID: 25455365 DOI: 10.1016/j.tips.2014.09.011] [Citation(s) in RCA: 146] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Revised: 09/29/2014] [Accepted: 09/30/2014] [Indexed: 11/26/2022]
Abstract
Adult hippocampal neurogenesis is implicated in antidepressant action, stress responses, and cognitive functioning. The hippocampus is functionally segregated along its longitudinal axis into dorsal (dHi) and ventral (vHi) regions in rodents, and analogous posterior and anterior regions in primates, whereby the vHi preferentially regulates stress and anxiety, while the dHi preferentially regulates spatial learning and memory. Given the role of neurogenesis in functions preferentially regulated by the dHi or vHi, it is plausible that neurogenesis is preferentially regulated in either the dHi or vHi depending upon the stimulus. We appraise here the literature on the effects of stress and antidepressants on neurogenesis along the hippocampal longitudinal axis and explore whether preferential regulation of neurogenesis in the vHi/anterior hippocampus contributes to stress resilience and antidepressant action.
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Affiliation(s)
- Olivia F O'Leary
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
| | - John F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
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Paterson C, Law AJ. Transient overexposure of neuregulin 3 during early postnatal development impacts selective behaviors in adulthood. PLoS One 2014; 9:e104172. [PMID: 25093331 PMCID: PMC4122441 DOI: 10.1371/journal.pone.0104172] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 07/08/2014] [Indexed: 02/06/2023] Open
Abstract
Neuregulin 3 (NRG3), a specific ligand for ErbB4 and a neuronal-enriched neurotrophin is implicated in the genetic predisposition to a broad spectrum of neurodevelopmental, neurocognitive and neuropsychiatric disorders, including Alzheimer's disease, autism and schizophrenia. Genetic studies in schizophrenia demonstrate that risk variants in NRG3 are associated with cognitive and psychotic symptom severity, accompanied by increased expression of prefrontal cortical NRG3. Despite our expanding knowledge of genetic involvement of NRG3 in neurological disorders, little is known about the neurodevelopmental mechanisms of risk. Here we exploited the fact that a paralog of NRG3, NRG1, readily penetrates the murine blood brain barrier (BBB). In this study we synthesized the bioactive epidermal growth factor (EGF) domain of NRG3, and using previously validated in-vivo peripheral injection methodologies in neonatal mice, demonstrate that NRG3 successfully crosses the BBB, where it activates its receptor ErbB4 and downstream Akt signaling at levels of bioactivity comparable to NRG1. To determine the impact of NRG3 overexpression during one critical developmental window, C57BL/6 male mice were subcutaneously injected daily with NRG1-EGF, NRG3-EGF or vehicle from postnatal days 2–10. Mice were tested in adulthood using a comprehensive battery of behavioral tasks relevant to neurocognitive and psychiatric disorders. In agreement with previous studies, developmental overexposure to NRG1 induced multiple non-CNS mediated peripheral effects as well as severely disrupting performance of prepulse inhibition of the startle response. In contrast, NRG3 had no effect on any peripheral measures investigated or sensorimotor gating. Specifically, developmental NRG3 overexposure produced an anxiogenic-like phenotype and deficits in social behavior in adulthood. These results provide primary data to support a role for NRG3 in brain development and function, which appears to be distinct from its paralog NRG1. Furthermore we demonstrate how perturbations in NRG3 expression at distinct developmental stages may contribute to the neurological deficits observed in brain disorders such as schizophrenia and autism.
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Affiliation(s)
- Clare Paterson
- Department of Psychiatry, University of Colorado, School of Medicine, Aurora, Colorado, United States of America
| | - Amanda J. Law
- Department of Psychiatry, University of Colorado, School of Medicine, Aurora, Colorado, United States of America
- Department of Cell and Developmental Biology, University of Colorado, School of Medicine, Aurora, Colorado, United States of America
- * E-mail:
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Radial Glia, the Keystone of the Development of the Hippocampal Dentate Gyrus. Mol Neurobiol 2014; 51:131-41. [DOI: 10.1007/s12035-014-8692-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 03/24/2014] [Indexed: 01/20/2023]
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Shruster A, Offen D. Targeting neurogenesis ameliorates danger assessment in a mouse model of Alzheimer's disease. Behav Brain Res 2013; 261:193-201. [PMID: 24388979 DOI: 10.1016/j.bbr.2013.12.028] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 12/17/2013] [Accepted: 12/21/2013] [Indexed: 01/21/2023]
Abstract
Alzheimer's disease (AD) affects 13% of the population over the age of 65. Behavioral and neuropsychiatric symptoms are frequent and affect 80% of patients. Adult hippocampal neurogenesis, which is impaired in AD, is involved in learning and memory. It remains unclear, however, whether increasing adult neurogenesis improves behavioral symptoms in AD. We report that in the 3xTgAD mouse model of AD, chronic Wnt3a overexpression in the ventral hippocampus dentate gyrus (DG) restored adult neurogenesis to physiological levels. The restoration of adult neurogenesis led to full recovery of danger assessment impairment and the effect was blocked by ablation of neurogenesis with X-irradiation. Finally, using a bed nucleus of stria terminalis (BNST) mRNA expression array, we found that the expression of the 5-HT1A receptor in 3xTgAD mice is selectively decreased and normalized by Wnt3a overexpression in the ventral hippocampus DG, and this normalization is neurogenesis dependent. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult AD mice rescues behavioral symptoms, suggesting that adult neurogenesis may be a promising therapeutic target for alleviating behavioral deficits in AD patients.
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Affiliation(s)
- Adi Shruster
- Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Petah Tikva, Israel.
| | - Daniel Offen
- Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Petah Tikva, Israel
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Ruan L, Lau BWM, Wang J, Huang L, Zhuge Q, Wang B, Jin K, So KF. Neurogenesis in neurological and psychiatric diseases and brain injury: from bench to bedside. Prog Neurobiol 2013; 115:116-37. [PMID: 24384539 DOI: 10.1016/j.pneurobio.2013.12.006] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 12/08/2013] [Accepted: 12/12/2013] [Indexed: 02/08/2023]
Abstract
Researchers who have uncovered the presence of stem cells in an adult's central nervous system have not only challenged the dogma that new neurons cannot be generated during adulthood, but also shed light on the etiology and disease mechanisms underlying many neurological and psychiatric disorders. Brain trauma, neurodegenerative diseases, and psychiatric disorders pose enormous burdens at both personal and societal levels. Although medications for these disorders are widely used, the treatment mechanisms underlying the illnesses remain largely elusive. In the past decade, an increasing amount of evidence indicate that adult neurogenesis (i.e. generating new CNS neurons during adulthood) may be involved in the pathology of different CNS disorders, and thus neurogenesis may be a potential target area for treatments. Although new neurons were shown to be a major player in mediating treatment efficacy of neurological and psychotropic drugs on cognitive functions, it is still debatable if the altered production of new neurons can cause the disorders. This review hence seeks to discuss pre and current clinical studies that demonstrate the functional impact adult neurogenesis have on neurological and psychiatric illnesses while examining the related underlying disease mechanisms.
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Affiliation(s)
- Linhui Ruan
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, TX 76107, USA.
| | - Benson Wui-Man Lau
- Department of Rehabilitation Science, The Hong Kong Polytechnic University, Hong Kong, PR China
| | - Jixian Wang
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, TX 76107, USA
| | - Lijie Huang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, TX 76107, USA
| | - Qichuan Zhuge
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Brian Wang
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, TX 76107, USA
| | - Kunlin Jin
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, TX 76107, USA.
| | - Kwok-Fai So
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, PR China; The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, PR China; Research Centre of Heart, Brain, Hormone and Healthy Aging, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, PR China; GMH Institute of CNS Regeneration, Jinan University, Guangzhou, PR China.
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Mahar I, Bambico FR, Mechawar N, Nobrega JN. Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neurosci Biobehav Rev 2013; 38:173-92. [PMID: 24300695 DOI: 10.1016/j.neubiorev.2013.11.009] [Citation(s) in RCA: 447] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 11/19/2013] [Accepted: 11/25/2013] [Indexed: 01/19/2023]
Abstract
Chronic stressful life events are risk factors for developing major depression, the pathophysiology of which is strongly linked to impairments in serotonin (5-HT) neurotransmission. Exposure to chronic unpredictable stress (CUS) has been found to induce depressive-like behaviours, including passive behavioural coping and anhedonia in animal models, along with many other affective, cognitive, and behavioural symptoms. The heterogeneity of these symptoms represents the plurality of corticolimbic structures involved in mood regulation that are adversely affected in the disorder. Chronic stress has also been shown to negatively regulate adult hippocampal neurogenesis, a phenomenon that is involved in antidepressant effects and regulates subsequent stress responses. Although there exists an enormous body of data on stress-induced alterations of 5-HT activity, there has not been extensive exploration of 5-HT adaptations occurring presynaptically or at the level of the raphe nuclei after exposure to CUS. Similarly, although hippocampal neurogenesis is known to be negatively regulated by stress and positively regulated by antidepressant treatment, the role of neurogenesis in mediating affective behaviour in the context of stress remains an active area of investigation. The goal of this review is to link the serotonergic and neurogenic hypotheses of depression and antidepressant effects in the context of stress. Specifically, chronic stress significantly attenuates 5-HT neurotransmission and 5-HT1A autoreceptor sensitivity, and this effect could represent an endophenotypic hallmark for mood disorders. In addition, by decreasing neurogenesis, CUS decreases hippocampal inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, exacerbating stress axis overactivity. Similarly, we discuss the possibility that adult hippocampal neurogenesis mediates antidepressant effects via the ventral (in rodents; anterior in humans) hippocampus' influence on the HPA axis, and mechanisms by which antidepressants may reverse chronic stress-induced 5-HT and neurogenic changes. Although data are as yet equivocal, antidepressant modulation of 5-HT neurotransmission may well serve as one of the factors that could drive neurogenesis-dependent antidepressant effects through these stress regulation-related mechanisms.
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Affiliation(s)
- Ian Mahar
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
| | | | - Naguib Mechawar
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - José N Nobrega
- Behavioural Neurobiology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada
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Neurogenesis along the septo-temporal axis of the hippocampus: Are depression and the action of antidepressants region-specific? Neuroscience 2013; 252:234-52. [DOI: 10.1016/j.neuroscience.2013.08.017] [Citation(s) in RCA: 166] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 07/01/2013] [Accepted: 08/12/2013] [Indexed: 01/25/2023]
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Cui W, Tao J, Wang Z, Ren M, Zhang Y, Sun Y, Peng Y, Li R. Neuregulin1beta1 antagonizes apoptosis via ErbB4-dependent activation of PI3-kinase/Akt in APP/PS1 transgenic mice. Neurochem Res 2013; 38:2237-46. [PMID: 23982319 DOI: 10.1007/s11064-013-1131-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 08/06/2013] [Accepted: 08/10/2013] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid protein (Aβ) and extensive neuronal cell death. Apoptosis plays a crucial role in loss of neurons in AD. Neuregulin1 (NRG1) has been found to protect neurons from oxygen glucose deprivation induced apoptosis and hypoxia ischemia induced apoptosis. However, the relationship between NRG1 and apoptosis related protein expression in AD and its mechanism remain uncertain. The present study explores the effects of NRG1 on Aβ-induced apoptosis in AD. In this study, extracellular domain of NRG1beta1 (NRG1β1-ECD) promoted the expression of p-ErbB4 receptor, p-Akt and increased the level of Bcl-2 both in APP/PS1 transgenic mice and in vitro. In primary culture of neurons, the level of Bcl-2 protein decreased significantly after Aβ treatment. These changes were inhibited by pretreatment of neurons with NRG1β1-ECD. A specific inhibitor of PI3-kinase/Akt pathway, wortmannin, significantly abrogated the effects of NRG1β1-ECD on p-Akt and Bcl-2 levels. Furthermore, the expression of PI3-kinase/Akt by NRG1β1-ECD was ErbB4-dependent. Our data demonstrated that NRG1β1-ECD might serve as an obvious neuroprotection in AD, and the possible protective mechanism occurs most likely via ErbB4-dependent activation of PI3-kinase/Akt pathway.
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Affiliation(s)
- Weigang Cui
- Key Open Lab for Tissue Regeneration of Henan Universities, Department of Human Anatomy, Xinxiang Medical University, Xinxiang, 453003, China
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40
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Tanti A, Westphal WP, Girault V, Brizard B, Devers S, Leguisquet AM, Surget A, Belzung C. Region-dependent and stage-specific effects of stress, environmental enrichment, and antidepressant treatment on hippocampal neurogenesis. Hippocampus 2013; 23:797-811. [DOI: 10.1002/hipo.22134] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2013] [Indexed: 11/11/2022]
Affiliation(s)
- Arnaud Tanti
- INSERM UMR930; Tours France
- Université François Rabelais; Tours France
| | | | - Virginie Girault
- INSERM UMR930; Tours France
- Université François Rabelais; Tours France
| | - Bruno Brizard
- INSERM UMR930; Tours France
- Université François Rabelais; Tours France
| | - Severine Devers
- INSERM UMR930; Tours France
- Université François Rabelais; Tours France
| | | | - Alexandre Surget
- INSERM UMR930; Tours France
- Université François Rabelais; Tours France
| | - Catherine Belzung
- INSERM UMR930; Tours France
- Université François Rabelais; Tours France
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Deng C, Pan B, Engel M, Huang XF. Neuregulin-1 signalling and antipsychotic treatment: potential therapeutic targets in a schizophrenia candidate signalling pathway. Psychopharmacology (Berl) 2013; 226:201-15. [PMID: 23389757 DOI: 10.1007/s00213-013-3003-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2012] [Accepted: 01/22/2013] [Indexed: 02/08/2023]
Abstract
Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)-ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1-ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1-ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1-ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or those with NRG1/ErbB4 over-expression, some of these abnormalities can be improved by antipsychotic treatment. NRG1-ErbB4 signalling has extensive interactions with the GABAergic, glutamatergic and dopaminergic neurotransmission systems that are involved in the pathophysiology of schizophrenia. These interactions provide a number of targets for the development of new antipsychotic drugs. Furthermore, the key interaction points between NRG1-ErbB4 signalling and other schizophrenia susceptibility genes may also potentially provide specific targets for new antipsychotic drugs. In general, identification of these targets in NRG1-ErbB4 signalling and interacting pathways will provide unique opportunities for the development of new generation antipsychotics with specific efficacy and fewer side effects.
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Affiliation(s)
- Chao Deng
- Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522 NSW, Australia.
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Iwakura Y, Nawa H. ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson's disease. Front Cell Neurosci 2013; 7:4. [PMID: 23408472 PMCID: PMC3570895 DOI: 10.3389/fncel.2013.00004] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Accepted: 01/08/2013] [Indexed: 12/15/2022] Open
Abstract
Ligands for ErbB1-4 receptor tyrosine kinases, such as epidermal growth factor (EGF) and neuregulins, regulate brain development and function. Thus, abnormalities in their signaling are implicated in the etiology or pathology of schizophrenia and Parkinson's disease. Among the ErbB receptors, ErbB1, and ErbB4 are expressed in dopamine and GABA neurons, while ErbB1, 2, and/or 3 are mainly present in oligodendrocytes, astrocytes, and their precursors. Thus, deficits in ErbB signaling might contribute to the neurological and psychiatric diseases stemming from these cell types. By incorporating the latest cancer molecular biology as well as our recent progress, we discuss signal cross talk between the ErbB1-4 subunits and their neurobiological functions in each cell type. The potential contribution of virus-derived cytokines (virokines) that mimic EGF and neuregulin-1 in brain diseases are also discussed.
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Affiliation(s)
- Yuriko Iwakura
- Division of Molecular Neurobiology, Brain Research Institute, Niigata University Niigata, Japan
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43
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Behavioral and neurobiological effects of prenatal stress exposure in male and female APPswe/PS1dE9 mice. Neurobiol Aging 2013; 34:319-37. [DOI: 10.1016/j.neurobiolaging.2012.05.012] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Revised: 05/21/2012] [Accepted: 05/21/2012] [Indexed: 11/18/2022]
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Sierksma ASR, Rutten K, Sydlik S, Rostamian S, Steinbusch HWM, van den Hove DLA, Prickaerts J. Chronic phosphodiesterase type 2 inhibition improves memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease. Neuropharmacology 2012; 64:124-36. [PMID: 22771768 DOI: 10.1016/j.neuropharm.2012.06.048] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 06/22/2012] [Accepted: 06/24/2012] [Indexed: 01/08/2023]
Abstract
Alzheimer's disease (AD) is characterized by progressive cognitive deficits and synaptic dysfunction. Over the last decade phosphodiesterase inhibitors (PDEIs) have received increasing attention as putative cognition enhancers and have been suggested as a novel treatment strategy for AD. Given their ability to prevent hydrolysis of cAMP and/or cGMP, they can stimulate the cAMP/protein kinase A (PKA)/cAMP element-binding protein (CREB) and cGMP/PKG/CREB pathway to enhance synaptic transmission by increasing CREB phosphorylation (pCREB) and brain-derived neurotrophic factor (BDNF) transcription. Based on previous research, we hypothesized that chronic PDE2I treatment would improve AD-related cognitive deficits, by decreasing amyloid-β (Aβ) plaque load, enhancing pCREB and BDNF levels and increasing synaptic density in the hippocampus of 8-month-old APPswe/PS1dE9 mice. Results indicated that chronic PDE2I treatment could indeed improve memory performance in APPswe/PS1dE9 mice, without affecting anxiety, depressive-like behavior or hypothalamus-pituitary-adrenal axis regulation. However, no treatment effects were observed on Aβ plaque load, pCREB or BDNF concentrations, or presynaptic density in the hippocampus, suggesting that other signaling pathways and/or effector molecules might be responsible for its cognition-enhancing effects. Presynaptic density in the stratum lucidum of the CA3 subregion was significantly higher in APPswe/PS1dE9 mice compared to WT controls, possibly reflecting a compensatory mechanism. In conclusion, PDEs in general, and PDE2 specifically, could be considered as promising therapeutic targets for cognition enhancement in AD, although the underlying mechanism of action remains to be elucidated. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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Affiliation(s)
- Annerieke S R Sierksma
- Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Science, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands
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Mahar I, Bagot RC, Davoli MA, Miksys S, Tyndale RF, Walker CD, Maheu M, Huang SH, Wong TP, Mechawar N. Developmental hippocampal neuroplasticity in a model of nicotine replacement therapy during pregnancy and breastfeeding. PLoS One 2012; 7:e37219. [PMID: 22615944 PMCID: PMC3352874 DOI: 10.1371/journal.pone.0037219] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Accepted: 04/15/2012] [Indexed: 11/18/2022] Open
Abstract
RATIONALE The influence of developmental nicotine exposure on the brain represents an important health topic in light of the popularity of nicotine replacement therapy (NRT) as a smoking cessation method during pregnancy. OBJECTIVES In this study, we used a model of NRT during pregnancy and breastfeeding to explore the consequences of chronic developmental nicotine exposure on cerebral neuroplasticity in the offspring. We focused on two dynamic lifelong phenomena in the dentate gyrus (DG) of the hippocampus that are highly sensitive to the environment: granule cell neurogenesis and long-term potentiation (LTP). METHODS Pregnant rats were implanted with osmotic mini-pumps delivering either nicotine or saline solutions. Plasma nicotine and metabolite levels were measured in dams and offspring. Corticosterone levels, DG neurogenesis (cell proliferation, survival and differentiation) and glutamatergic electrophysiological activity were measured in pups. RESULTS Juvenile (P15) and adolescent (P41) offspring exposed to nicotine throughout prenatal and postnatal development displayed no significant alteration in DG neurogenesis compared to control offspring. However, NRT-like nicotine exposure significantly increased LTP in the DG of juvenile offspring as measured in vitro from hippocampal slices, suggesting that the mechanisms underlying nicotine-induced LTP enhancement previously described in adult rats are already functional in pups. CONCLUSIONS These results indicate that synaptic plasticity is disrupted in offspring breastfed by dams passively exposed to nicotine in an NRT-like fashion.
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Affiliation(s)
- Ian Mahar
- Departments of Psychiatry, Neurology and Neurosurgery, Douglas Mental Health University Institute, McGill University, Verdun, Québec, Canada
| | - Rosemary C. Bagot
- Departments of Psychiatry, Neurology and Neurosurgery, Douglas Mental Health University Institute, McGill University, Verdun, Québec, Canada
| | - Maria Antonietta Davoli
- Departments of Psychiatry, Neurology and Neurosurgery, Douglas Mental Health University Institute, McGill University, Verdun, Québec, Canada
| | - Sharon Miksys
- Departments of Pharmacology and Toxicology and Psychiatry, Centre for Addiction and Mental Health and University of Toronto, Medical Sciences Building, Toronto, Ontario, Canada
| | - Rachel F. Tyndale
- Departments of Pharmacology and Toxicology and Psychiatry, Centre for Addiction and Mental Health and University of Toronto, Medical Sciences Building, Toronto, Ontario, Canada
| | - Claire-Dominique Walker
- Departments of Psychiatry, Neurology and Neurosurgery, Douglas Mental Health University Institute, McGill University, Verdun, Québec, Canada
| | - Marissa Maheu
- Departments of Psychiatry, Neurology and Neurosurgery, Douglas Mental Health University Institute, McGill University, Verdun, Québec, Canada
| | - Sheng-Hai Huang
- Department of Microbiology, College of Basic Medicine, Anhui Medical University, Hefei, Anhui, People's Republic of China
| | - Tak Pan Wong
- Departments of Psychiatry, Neurology and Neurosurgery, Douglas Mental Health University Institute, McGill University, Verdun, Québec, Canada
- Department of Pharmacology & Therapeutics, Douglas Mental Health University Institute, McGill University, Verdun, Québec, Canada
| | - Naguib Mechawar
- Departments of Psychiatry, Neurology and Neurosurgery, Douglas Mental Health University Institute, McGill University, Verdun, Québec, Canada
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Szamosi A, Kelemen O, Kéri S. Hippocampal volume and the AKT signaling system in first-episode schizophrenia. J Psychiatr Res 2012; 46:279-84. [PMID: 22209534 DOI: 10.1016/j.jpsychires.2011.12.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Revised: 12/09/2011] [Accepted: 12/12/2011] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The phosphoinositide 3'-kinase (PI3K)--protein kinase B (AKT1)--glycogen synthase kinase (GSK)-3β system is modulated by several factors implicated in the pathophysiology of schizophrenia. Evidence suggests that neuregulin 1 (NRG1) induces decreased AKT phosphorylation in schizophrenia relative to healthy controls, which may be related to dysfunctional neurodevelopment and neuroplasticity. The aim of this study was to investigate the relationship between NRG1--induced AKT phosphorylation and hippocampal volume in schizophrenia. METHODS Participants were 20 first-episode patients with schizophrenia who did not receive psychotropic medications and 20 matched healthy controls. We measured the phosphorylated AKT--total AKT and phosphorylated ERK (extracellular signal-regulated kinase)--total ERK ratios in peripheral lymphoblasts before and after NRG1 administration. Whole-brain, left, and right hippocampal volumes were quantified using FreeSurfer software. RESULTS Patients with schizophrenia displayed decreased AKT but normal ERK ratio compared with controls. Patients also had a reduction in left hippocampal volume. There was no significant difference between patients and controls in whole-brain and right hippocampal volume. Decreased AKT ratio was associated with reduced hippocampal volume. There was no significant relationship between ERK ratio and brain structure. CONCLUSION Activation of the AKT system is specifically associated with hippocampal volume in first-episode schizophrenia, which provides further evidence for the pivotal role of this messenger system in the pathophysiology of psychotic disorders.
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