Activation and Regulation of the Synaptic Receptor BAI1

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Project Summary Schizophrenia is a devastating psychiatric disorder that affects ~1% of the USA population. Over the past few decades, twin studies and other genetic analyses have established that approximately 80% of schizophrenia risk is due to heritability, but at present only a small number of genes have been definitively linked to this clearly polygenic disorder. Thus, the identification of additional genes that contribute to schizophrenia risk can provide new insights about the disease and also suggest potential new avenues for treatment. Recently, whole-exome analyses of an extensive set of multiplex schizophrenia families revealed several mutations in the brain angiogenesis inhibitor 1 (BAI1) to be associated with schizophrenia. BAI1 is a synaptic receptor known to regulate dendritic spines and synaptic plasticity, and the BAI1 mutations linked to schizophrenia in these analyses are all missense mutations with extremely high CADD scores. We will assess the effects of these schizophrenia-associated mutations on the trafficking and signaling activity of BAI1 in order to determine how these mutations may be contributing to the development of schizophrenia. The signaling studies will assess the effects of the mutations on both i) constitutive signaling activity by the receptor and ii) signaling stimulated by co-expression of BAI1 with phospholipid scramblases. In parallel studies, we will determine whether this scramblase-mediated potentiation of BAI1 signaling is due to externalization of phosphatidylserine, a previously reported ligand for the extracellular domains of BAI1. Thus, the proposed studies will shed new light on the fundamental biology of BAI1 while also assessing the functional effects of the schizophrenia-associated BAI1 mutations, with the goal of facilitating the eventual targeting of this receptor by small molecule therapeutics that may be useful new treatments for schizophrenia and other psychiatric disorders. ! !