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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Gene Expression Omnibus

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


  1. 1.

    Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 44, 660–669 (1987)

  2. 2.

    , , & Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Trends Neurosci. 24, 479–486 (2001)

  3. 3.

    , & SNARE proteins and schizophrenia: linking synaptic and neurodevelopmental hypotheses. Acta Biochim. Pol. 55, 619–628 (2008)

  4. 4.

    & Presynaptic proteins and schizophrenia. Int. Rev. Neurobiol. 59, 175–199 (2004)

  5. 5.

    et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154, 518–529 (2013)

  6. 6.

    et al. Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders. Mol. Psychiatry 19, 872–879 (2014)

  7. 7.

    et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72, 951–963 (2011)

  8. 8.

    et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014)

  9. 9.

    et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014)

  10. 10.

    et al. Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia. Mol. Psychiatry 17, 996–1006 (2012)

  11. 11.

    , & Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nature Rev. Genet. 13, 537–551 (2012)

  12. 12.

    et al. A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol. Psychiatry 10, 758–764 (2005)

  13. 13.

    et al. DISC1 genetics, biology and psychiatric illness. Front. Biol. 8, 1–31 (2013)

  14. 14.

    et al. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 130, 1146–1158 (2007)

  15. 15.

    , & Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders. Front. Biol. 7, 179–188 (2012)

  16. 16.

    et al. Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Mol. Psychiatry 16, 358–360 (2011)

  17. 17.

    et al. Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum. Mol. Genet. 20, 4666–4683 (2011)

  18. 18.

    et al. Insolubility of disrupted-in-schizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease. J. Neurosci. 28, 3839–3845 (2008)

  19. 19.

    , , & Synaptic vesicle protein 2 enhances release probability at quiescent synapses. J. Neurosci. 26, 1303–1313 (2006)

  20. 20.

    & SV2 renders primed synaptic vesicles competent for Ca2+-induced exocytosis. J. Neurosci. 29, 883–897 (2009)

  21. 21.

    et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010)

  22. 22.

    et al. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol. Psychiatry 12, 74–86 (2007)

  23. 23.

    , , , & Synapsin I injected presynaptically into goldfish mauthner axons reduces quantal synaptic transmission. J. Neurophysiol. 63, 701–706 (1990)

  24. 24.

    et al. Short-term synaptic plasticity is altered in mice lacking synapsin I. Cell 75, 661–670 (1993)

  25. 25.

    et al. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311, 1008–1012 (2006)

  26. 26.

    et al. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc. Natl Acad. Sci. USA 105, 9391–9396 (2008)

  27. 27.

    , & Enhancing induced pluripotent stem cell models of schizophrenia. JAMA Psychiatry 71, 334–335 (2014)

  28. 28.

    et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011)

  29. 29.

    et al. Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Reports 2, 295–310 (2014)

  30. 30.

    et al. Phenotypic differences in hiPS cells NPCs derived from patients with schizophrenia. Mol. Psychiatry (2014)

  31. 31.

    et al. Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington’s disease patient cells. Mol. Brain 5, 17 (2012)

  32. 32.

    et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323, 1074–1077 (2009)

  33. 33.

    et al. Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting. Nucleic Acids Res. 39, e82 (2011)

  34. 34.

    , & Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nature Neurosci. 5, 438–445 (2002)

  35. 35.

    et al. NeurphologyJ: an automatic neuronal morphology quantification method and its application in pharmacological discovery. BMC Bioinformatics 12, 230 (2011)

  36. 36.

    et al. Transcript assembly and quantification by RNA-seq reveals unannotated transcripts and isoform switching during cell differentiation. Nature Biotechnol. 28, 511–515 (2010)

  37. 37.

    & Fast gapped-read alignment with Bowtie 2. Nature Methods 9, 357–359 (2012)

  38. 38.

    , & RSeQC: quality control of RNA-seq experiments. Bioinformatics 28, 2184–2185 (2012)

  39. 39.

    , & edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010)

  40. 40.

    , , & WEB-based gene set analysis toolkit (WebGestalt): update 2013. Nucleic Acids Res. 41, W77–W83 (2013)

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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.


  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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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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