Synaptic Functions of Disrupted-in-Schizophrenia-1 (DISC1)

DESCRIPTION (provided by applicant): Disrupted-in-Schizophrenia 1 (DISC1) is a genetic risk factor for schizophrenia and related mental illnesses, however the synaptic functions of DISC1 in mature neurons are largely unknown. Emerging evidence suggests that alterations of synaptic transmission might be the core feature and fundamental pathology of schizophrenia, thus the goal of this project is to understand the role of DISC1 in regulating synaptic protein functions in prefrontal cortical (PFC) neurons. We hypothesize that DISC1 exerts an important impact on synaptic transmission and plasticity by regulating NMDAR and GABAAR channels, two key targets involved in cognitive and emotional processes, and the synaptic function of DISC1 is altered in schizophrenia. Two specific aims will be addressed to examine the impact of DISC1 on the expression, trafficking and function of NMDARs and GABAARs in rat PFC neurons, using in vitro and in vivo knockdown of DISC1 or overexpression of full-length or C-terminal truncated DISC1. The potential mechanisms for DISC1 regulation of NMDARs and GABAARs will also be explored. Our results would not only reveal significant mechanistic insights into the synaptic functions of DISC1, but may also provide novel targets for more effective therapeutic strategies to treat mental disorders.