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
RNA-seq data were deposit at GEO (accession number: GSE57821).
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.
Extended data figures
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.
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.
About this article
Molecular Psychiatry (2019)