Journal Article

Synaptic dysregulation in a human iPS cell model of mental disorders

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

2014

Overview

Generation and neural differentiation of induced pluripotent stem cells (iPS cells) from patients enables new ways to investigate the cellular pathophysiology of mental disorders; this approach was used with samples from a family with a schizophrenia pedigree and a DISC1 mutation, revealing synaptic abnormalities and large-scale transcriptional dysregulation. DISC1 gene linked to synaptic dysfunction Although altered synaptic function and development are believed to underlie psychiatric disorders such as schizophrenia, evidence from human brains has been largely indirect. In vitro models derived from induced pluripotent stem cells (iPSCs) provide a promising means of study, but the genetic variability and complexity of many psychiatric disorders is a major source of difficulty in interpretation of phenotypes. Hongjun Song and colleagues generate iPSCs from members of a single family in which carriers of mutations in the DISC1 gene are linked to psychiatric disorders. They confirm that neurons carrying mutant DISC1 have synaptic dysfunction, and that these deficits can not only be rescued by correcting the mutation, but also recapitulated in control neurons by introducing the mutation with genome editing. Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders 1 , and ‘a disease of synapses’ is the major hypothesis for the biological basis of schizophrenia 2 . Although this hypothesis has gained indirect support from human post-mortem brain analyses 2 , 3 , 4 and genetic studies 5 , 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 phenotypes 11 . 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 12 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/100 / 13/106 / 38 / 38/39 / 631/378/1689/2608 / 64 / Animals / Bipolar disorder / Cell Differentiation / Fibroblasts / Genetics / Glutamine - metabolism / Health aspects / Humanities and Social Sciences / Humans / Hypotheses / Induced Pluripotent Stem Cells - metabolism / Induced Pluripotent Stem Cells - pathology / letter / Male / Mental disorders / Mental Disorders - genetics / Mental Disorders - metabolism / Mental Disorders - pathology / Mental illness / Mice / multidisciplinary / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutation / Mutation - genetics / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neurons / Neurons - cytology / Neurons - metabolism / Neurons - pathology / Pedigree / Presynaptic Terminals - metabolism / Presynaptic Terminals - pathology / Prosencephalon - metabolism / Prosencephalon - pathology / Protein Binding / Proteins / Schizophrenia / Science / Synapses - metabolism / Synapses - pathology / Transcriptome