STIMULATION OF SYNAPTIC VESICLE EXOCYTOSIS BY THE MENTAL ILLNESS GENE DISC1 IS MEDIATED BY N-TYPE VOLTAGE-GATED CALCIUM CHANNELS

Abstract

Mutations in the Disrupted-In-Schizophrenia 1 (DISC1) gene have been implicated in major psychiatric disorders. Recent studies reported DISC1 effects on the glutamatergic neurotransmitter (NT) system, which has been linked to schizophrenia. However, the molecular mechanism underlying these observations is unknown. To investigate the impact of DISC1 loss of function on neurotransmission, the synaptic vesicle (SV) cycle was examined at the hippocampal synapses using the synaptic tracer vGlut1-pHluorin under two independent genetic perturbations - RNAi and a DISC1 knockout mouse. Population imaging of these synapses revealed a significant reduction in SV exocytosis rates during synaptic stimulation. This reduction was accompanied by a decrease in presynaptic Ca2+ influx, an important determinant of NT release probability. Further, DISC1 was demonstrated to boost SV exocytosis through the N-type voltage-gated Ca2+ channel. Based on these results, a working model whereby DISC1 promotes NT release through increasing Cav2.2-dependent presynaptic Ca2+ influx during synaptic stimulation is proposed.