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Synaptic dysregulation in a human iPS cell model of mental disorders
Open accessAbstract
Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and 'a disease of synapses' is the major hypothesis for the biological basis of schizophrenia. Although this hypothesis has gained indirect support from human post-mortem brain analyses and genetic studies, little is known about the pathophysiology of synapses in patient neurons and how susceptibility genes for mental disorders could lead to synaptic deficits in humans. Genetics of most psychiatric disorders are extremely complex due to multiple susceptibility variants with low penetrance and variable phenotypes. Rare, multiply affected, large families in which a single genetic locus is probably responsible for conferring susceptibility have proven invaluable for the study of complex disorders. Here we generated induced pluripotent stem (iPS) cells from four members of a family in which a frameshift mutation of disrupted in schizophrenia 1 (DISC1) co-segregated with major psychiatric disorders and we further produced different isogenic iPS cell lines via gene editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPS-cell-derived forebrain neurons. Mutant DISC1 depletes wild-type DISC1 protein and, furthermore, dysregulates expression of many genes related to synapses and psychiatric disorders in human forebrain neurons. Our study reveals that a psychiatric disorder relevant mutation causes synapse deficits and transcriptional dysregulation in human neurons and our findings provide new insight into the molecular and synaptic etiopathology of psychiatric disorders.
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“SV2, a marker for mature synaptic vesicles and regulates presynaptic release (70, 71)”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [70]
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Metadata
- Authors
- Wen, Z., Nguyen, H. N., Guo, Z., Lalli, M. A., Wang, X., Su, Y., Kim, N.-S., Yoon, K.-J., Shin, J., Zhang, C., Makri, G., Nauen, D., Yu, H., Guzman, E., Chiang, C.-H., Yoritomo, N., Kaibuchi, K., Zou, J., Christian, K. M., Cheng, L., Ross, C. A., Margolis, R. L., Chen, G., Kosik, K. S., Song, H., & Ming, G.-L.
- Affiliations
- Johns Hopkins University (US)
- Pennsylvania State University (US)
- University of California, Santa Barbara (US)
- Nagoya University (JP)
- Corresponding author
- Ming, Guo-li
- ORCID
- Wen, Zhexing
- Nguyen, Ha Nam
- Guo, Ziyuan
- Lalli, Matthew A.
- Wang, Xinyuan
- Su, Yijing
- Kim, Nam-Shik
- Yoon, Ki-Jun
- Shin, Jaehoon
- Zhang, Ce
- Makri, Georgia
- Nauen, David
- Yu, Huimei
- Guzman, Elmer
- Yoritomo, Nadine
- Kaibuchi, Kozo
- Zou, Jizhong
- Christian, Kimberly M.
- Cheng, Linzhao
- Ross, Christopher A.
- Margolis, Russell L.
- Chen, Gong
- Kosik, Kenneth S.
- Song, Hongjun
- Ming, Guo-li
- Venue
- Nature
- Published
- 2014-08-17
- Volume
- 515
- Issue
- 7527
- Pages
- 414-418
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4501856
- OpenAlex
- W1968461255
- Cited by
- 549
- References
- 40
- Citations by year
- 2026: 29 · 2025: 31 · 2024: 26 · 2023: 34 · 2022: 38 · 2021: 50 · 2020: 53 · 2019: 46 · 2018: 58 · 2017: 58 · 2016: 60 · 2015: 62 · 2014: 4
- FWCI
- 25.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (AG045656, R01AG045656, R01AG024984)
- National Institute of Mental Health (R01MH083911, R21MH087874, R33MH087874, R21MH092740, MH087874, MH102978, R01MH105128, F31MH102978)
- National Institute of General Medical Sciences (T32GM008752)
- National Institute of Neurological Disorders and Stroke (NS 048271, R01NS047344, NS 047344, R01NS048271, R37NS047344, R56NS047344)
- National Institute of Environmental Health Sciences (R21ES021957)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- DISC1, schizophrenia, induced pluripotent stem cells, synaptic dysfunction, synaptic vesicle release, transcriptional dysregulation, forebrain neurons, isogenic cell lines, genome editing, mental illness, brain development
- MeSH terms
- Animals, Mental Disorders, Cell Differentiation, Fibroblasts, Glutamine, Humans, Male, Mutation, Nerve Tissue Proteins, Neurons, Pedigree, Protein Binding, Synapses, Prosencephalon, Presynaptic Terminals, Mutant Proteins, Mice, Induced Pluripotent Stem Cells, Transcriptome
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