Modeling Psychiatric Disorders Using Patient-derived Induced Pluripotent Stem Cells

Schizophrenia and autism spectrum disorder (ASD) are characterized by complex genetics, variable symptomatology, and anatomically distributed pathology, all of which have made identifying the etiology of these diseases extremely challenging. In addition, our understanding of the role of risk genes in mental disorders has been severely hindered by the lack of access to human neurons. Human induced pluripotent stem cells (iPSCs) derived from patients provide a unique opportunity to investigate the etiology and pathogenesis of these psychiatric disorders. Here, we report the generation and characterization of iPSCs derived from subjects with 15q11.2 copy-number variants (CNVs) and a frameshift mutation in Disrupted in Schizophrenia 1 (DISC1)—both types of mutations are associated with increased risk for schizophrenia and ASD. Mutant iPSCs differentiated toward cortical forebrain lineage revealed dysregulation of neural development and synaptic function. First, iPSC-derived neural progenitors from subjects carrying a 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. Second, using isogenic cell lines with and without a specific 4-basepair deletion in DISC1, we show that iPSC-derived forebrain neurons with the DISC1 mutation exhibit functional abnormalities including synaptic transmission deficits and dysregulated expression of many genes related to synaptic function and implicated in psychiatric disorders. Together these iPSC-based investigations of development and function of human neurons demonstrate the capability of this technology for identifying the biological processes and cellular pathways that are impacted by genetic risk for psychiatric disorders