Abstract
Severe psychiatric illnesses, such as schizophrenia and major depression, are chronic and complicated neurological diseases with a prominent genetic basis. However, the causes of these mental disorders are still poorly understood due to the lack of a representative model that accurately recapitulates the nature and distribution of the human pathology. Human induced-pluripotent stem cells (iPSCs), which carry the genetic information from patients, pave the way to study human development and to discover the molecular and cellular basis of human diseases in a more tractable experimental system. Here we generated iPSCs from four members of a family in which a frame-shift mutation of Disrupted-in-schizophrenia 1 (DISC1) co-segregated with psychiatric disorders. We further produced different isogenic iPSC lines with TALEN genome editing technique. We show that mutant DISC1 leads to deficits in presynaptic vesicle release in human forebrain neurons. Mechanistically, mutant DISC1 causes transcriptional dysregulation of many genes related to synapses and psychiatric disorders and depletes wild-type DISC1. Furthermore, mechanism-guided pharmacological inhibition of phosphodiesterases rescues synaptic defects in mutant neurons. Our studies directly support the synapse hypothesis for the etiopathology of psychiatric disorders and uncover a novel mechanism through which the disease-relevant mutation affects synaptic functions via transcriptional dysregulation.