Description:

Abstract:

Schizophrenia, autism spectrum disorder, bipolar disease, and epilepsy are genetically related and highly debilitating neurodevelopmental disorders that affect >3% of the world population. Current therapies for these diseases do not ameliorate all symptoms for those who suffer from these disorders. Further, therapies have not improved in efficacy in decades. Our overarching goal is to provide a better understanding of these disorders as a basis to discover new therapies to better drugs to treat these disorders. 

Genetic variants in the TRIO gene increase risk for neurodevelopmental disorders (NDDs) including schizophrenia, autism, and related disorders. TRIO encodes a large protein with two guanine nucleotide exchange factor (GEF) domains for Rho family GTPases: GEF1 activates Rac1 and RhoG, and GEF2 activates RhoA. I will describe our work along three fronts: 1) how do the diverse NDD-related variants in TRIO differentially affect its biochemical functions? 2) what intracellular neuronal signaling pathways are altered by these changes in TRIO function? and 3) how do these selective changes differentially impact mouse brain development and behavior?

Our identification and characterization of these mechanisms will provide the essential first steps in translating emerging genetic risk factors into new therapeutic approaches.