2012-13 SEMINAR SERIES Dr. GuopingFeng “Probing Synaptic and Circuitry Mechanisms of Psychiatric Disorders” Thursday, April 4, 2013 11:00 am – 12:00 pm MPFI Auditorium Hosted by McLean Bolton, PhD GuopingFeng, PhD Professor, Dept. of Brain & Cognitive Science Massachusetts Institute of Technology Abstract: Recent human genetic and genomic studies have identified a large number of candidate genes for obsessive-compulsive disorder (OCD), autism spectrum disorders (ASDs), and schizophrenia, many of which encode postsynaptic scaffolding proteins including MAGUK, SAPAP, and SHANK families of proteins. These groups of multidomain proteins form a key scaffold, orchestrating the assembly of the macromolecular postsynaptic complex at excitatory synapses. This complex has been proposed to play key roles in targeting, anchoring, and dynamically regulating synaptic localization of neurotransmitter receptors and signaling molecules. Using genetically modified mice as a model system, we explore how mutations in these genes lead to synaptic dysfunction and abnormal behaviors relevant to OCD and ASDs. We find that both SAPAP3 and SHANK3 proteins are highly expressed at cortico-striatal synapses, part of the neural circuit strongly implicated as being dysfunctional in OCD and ASDs. Genetic deletion of SAPAP3 or SHANK3 leads to repetitive/compulsive behaviors in mice. Furthermore, SHANK3 mutant mice display profound social deficits. Morphological, biochemical, and electrophysiological studies all point to defects at the glutamatergiccortico-striatal synapses. Our findings suggest a common synaptic and circuitry mechanism for some of the abnormal behaviors relevant to OCD and ASDs.