Abstract

Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders1, and ‘a disease of synapses’ is the major hypothesis for the biological basis of schizophrenia2. Although this hypothesis has gained indirect support from human post-mortem brain analyses2,3,4 and genetic studies5,6,7,8,9,10, 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 phenotypes11. 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 disorders12 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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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

RNA-seq data were deposit at GEO (accession number: GSE57821).

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Acknowledgements

We thank members of Ming and Song laboratories for discussion, and Q. Hussaini, Y. Cai and L. Liu for technical support. This work was supported by grants from the NIH (MH087874, NS047344), IMHRO, SFARI, NARSAD, and MSCRF to H.S.; from MSCRF, NARSAD and the NIH (NS048271) to G.-l.M.; from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to G.-l.M. and K.S.K.; from the NIH (AG045656) to G.C.; from MSCRF and NARSAD to K.M.C.; by postdoctoral fellowships from MSCRF to Z.W., Y.S., N.S.K., and G.M.; and by a predoctoral fellowship from the NIH (MH102978) to H.N.N.

Author information

Author notes

    • Zhexing Wen
    • , Ha Nam Nguyen
    •  & Ziyuan Guo

    These authors contributed equally to this work.

    • Russell L. Margolis
    • , Gong Chen
    • , Kenneth S. Kosik
    • , Hongjun Song
    •  & Guo-li Ming

    These authors jointly supervised this work.

Affiliations

  1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Zhexing Wen
    • , Ha Nam Nguyen
    • , Xinyuan Wang
    • , Yijing Su
    • , Nam-Shik Kim
    • , Ki-Jun Yoon
    • , Jaehoon Shin
    • , Ce Zhang
    • , Georgia Makri
    • , David Nauen
    • , Huimei Yu
    • , Cheng-Hsuan Chiang
    • , Jizhong Zou
    • , Kimberly M. Christian
    • , Linzhao Cheng
    • , Hongjun Song
    •  & Guo-li Ming
  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Zhexing Wen
    • , Yijing Su
    • , Nam-Shik Kim
    • , Ki-Jun Yoon
    • , Ce Zhang
    • , Georgia Makri
    • , Huimei Yu
    • , Cheng-Hsuan Chiang
    • , Kimberly M. Christian
    • , Hongjun Song
    •  & Guo-li Ming
  3. Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Ha Nam Nguyen
    • , Jaehoon Shin
    • , Christopher A. Ross
    • , Russell L. Margolis
    • , Hongjun Song
    •  & Guo-li Ming
  4. Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA

    • Ziyuan Guo
    •  & Gong Chen
  5. Neuroscience Research Institute, Department of Molecular Cellular and Developmental Biology, Biomolecular Science and Engineering Program, University of California, Santa Barbara, California 93106, USA

    • Matthew A. Lalli
    • , Elmer Guzman
    •  & Kenneth S. Kosik
  6. School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

    • Xinyuan Wang
  7. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • David Nauen
  8. The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Cheng-Hsuan Chiang
    • , Christopher A. Ross
    • , Russell L. Margolis
    • , Hongjun Song
    •  & Guo-li Ming
  9. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Nadine Yoritomo
    • , Christopher A. Ross
    •  & Russell L. Margolis
  10. Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8550, Japan

    • Kozo Kaibuchi
  11. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Jizhong Zou
    •  & Linzhao Cheng

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Contributions

Z.W. led and was involved in every aspect of the project. H.N.N. generated isogenic iPS cell lines. Z.G. and G.C. performed electrophysiology analyses. M.A.L., E.G. and K.S.K. performed RNA-seq analyses. X.W., Y.S., N.-S.K., K.-J.Y., J.S., C.Z., G.M., D.N., H.Y., C.-H.C. and K.M.C. helped with data collection. K.K. provided DISC1 antibodies. N.Y., C.A.R. and R.L.M. obtained original skin biopsies from pedigree H.J.Z. and L.C. helped with TALEN design. G.-l.M., H.S. and Z.W. designed the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Guo-li Ming.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    Summary of iPSC lines and reagents used in the current study. a, Summary of characterization of all iPSC lines used. b, Summary of information for antibodies used. c, List of primer sequences.

  2. 2.

    Supplementary Table 2

    Summary of RNA-seq analysis of 4 week-old forebrain neurons from D2-1, D3-2 and C3-1 iPSC lines. a, RNA-seq read information. b, List of common up-regulated genes in DISC1 mutant D2-1 and D3-2 forebrain neurons compared to control C3-1 neurons. c, List of common down-regulated genes in DISC1 mutant D2-1 and D3-2 forebrain neurons compared to control C3-1 neurons; d, List of differentially expressed genes related to synapses; e, List of differentially expressed genes related to mental disorders.

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DOI

https://doi.org/10.1038/nature13716

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