Synaptic dysregulation in a human iPS cell model of mental disorders

Zhexing Wen, Ha Nam Nguyen, Ziyuan Guo, Matthew A. Lalli, Xinyuan Wang, Yijing Su, Nam Shik Kim, Ki Jun Yoon, Jaehoon Shin, Ce Zhang, Georgia Makri, David Nauen, Huimei Yu, Elmer Guzman, Cheng Hsuan Chiang, Nadine Yoritomo, Kozo Kaibuchi, Jizhong Zou, Kimberly M. Christian, Linzhao ChengChristopher A. Ross, Russell L. Margolis, Gong Chen, Kenneth S. Kosik, Hongjun Song, Guo Li Ming

Research output: Contribution to journalArticle

238 Citations (Scopus)

Abstract

Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and â € a disease of synapsesâ €™ 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.

Original languageEnglish (US)
Pages (from-to)414-418
Number of pages5
JournalNature
Volume515
Issue number7527
DOIs
StatePublished - Nov 20 2014

Fingerprint

Induced Pluripotent Stem Cells
Mental Disorders
Psychiatry
Schizophrenia
Synapses
Neurons
Prosencephalon
Frameshift Mutation
Genetic Loci
Penetrance
Synaptic Vesicles
Phenotype
Gene Expression
Cell Line
Mutation
Brain
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Wen, Z., Nguyen, H. N., Guo, Z., Lalli, M. A., Wang, X., Su, Y., ... Ming, G. L. (2014). Synaptic dysregulation in a human iPS cell model of mental disorders. Nature, 515(7527), 414-418. https://doi.org/10.1038/nature13716
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 ; Chiang, Cheng Hsuan ; 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. / Synaptic dysregulation in a human iPS cell model of mental disorders. In: Nature. 2014 ; Vol. 515, No. 7527. pp. 414-418.
@article{6d259a46e8d4464cb312f59104360a37,
title = "Synaptic dysregulation in a human iPS cell model of mental disorders",
abstract = "Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and {\^a} € a disease of synapses{\^a} €™ 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.",
author = "Zhexing Wen and Nguyen, {Ha Nam} and Ziyuan Guo and Lalli, {Matthew A.} and Xinyuan Wang and Yijing Su and Kim, {Nam Shik} and Yoon, {Ki Jun} and Jaehoon Shin and Ce Zhang and Georgia Makri and David Nauen and Huimei Yu and Elmer Guzman and Chiang, {Cheng Hsuan} and Nadine Yoritomo and Kozo Kaibuchi and Jizhong Zou and Christian, {Kimberly M.} and Linzhao Cheng and Ross, {Christopher A.} and Margolis, {Russell L.} and Gong Chen and Kosik, {Kenneth S.} and Hongjun Song and Ming, {Guo Li}",
year = "2014",
month = "11",
day = "20",
doi = "10.1038/nature13716",
language = "English (US)",
volume = "515",
pages = "414--418",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7527",

}

Wen, Z, Nguyen, HN, Guo, Z, Lalli, MA, Wang, X, Su, Y, Kim, NS, Yoon, KJ, Shin, J, Zhang, C, Makri, G, Nauen, D, Yu, H, Guzman, E, Chiang, CH, Yoritomo, N, Kaibuchi, K, Zou, J, Christian, KM, Cheng, L, Ross, CA, Margolis, RL, Chen, G, Kosik, KS, Song, H & Ming, GL 2014, 'Synaptic dysregulation in a human iPS cell model of mental disorders', Nature, vol. 515, no. 7527, pp. 414-418. https://doi.org/10.1038/nature13716

Synaptic dysregulation in a human iPS cell model of mental disorders. / 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; Chiang, Cheng Hsuan; 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.

In: Nature, Vol. 515, No. 7527, 20.11.2014, p. 414-418.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synaptic dysregulation in a human iPS cell model of mental disorders

AU - Wen, Zhexing

AU - Nguyen, Ha Nam

AU - Guo, Ziyuan

AU - Lalli, Matthew A.

AU - Wang, Xinyuan

AU - Su, Yijing

AU - Kim, Nam Shik

AU - Yoon, Ki Jun

AU - Shin, Jaehoon

AU - Zhang, Ce

AU - Makri, Georgia

AU - Nauen, David

AU - Yu, Huimei

AU - Guzman, Elmer

AU - Chiang, Cheng Hsuan

AU - Yoritomo, Nadine

AU - Kaibuchi, Kozo

AU - Zou, Jizhong

AU - Christian, Kimberly M.

AU - Cheng, Linzhao

AU - Ross, Christopher A.

AU - Margolis, Russell L.

AU - Chen, Gong

AU - Kosik, Kenneth S.

AU - Song, Hongjun

AU - Ming, Guo Li

PY - 2014/11/20

Y1 - 2014/11/20

N2 - Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and â € a disease of synapsesâ €™ 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.

AB - Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and â € a disease of synapsesâ €™ 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.

UR - http://www.scopus.com/inward/record.url?scp=84911360325&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84911360325&partnerID=8YFLogxK

U2 - 10.1038/nature13716

DO - 10.1038/nature13716

M3 - Article

C2 - 25132547

AN - SCOPUS:84911360325

VL - 515

SP - 414

EP - 418

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7527

ER -

Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature. 2014 Nov 20;515(7527):414-418. https://doi.org/10.1038/nature13716