PROJECT SUMMARY Excitatory ionotropic synapses and their associated dendritic spines play critical roles in fundamental information processing within the brain. The development and morphology of these synapses are highly functionally relevant; previous studies have established that patients with many different neurodevelopmental, neurodegenerative, and neuropsychiatric conditions are clinically defined by synaptopathies. Synaptopathies, or disease at the level of the synapse, includes inappropriate loss of synapses and spines, enhanced or lowered synapse and spine development, and aberrations to the synaptic structure that leads to dysfunctional signaling. The Brain-specific angiogenesis inhibitor (BAI) subfamily of neuronal adhesion G-protein coupled receptors (aGPCRs) are a three-member postsynaptic family of receptors predicted to form trans-synaptic complexes to direct synaptogenesis and synapse structural development. BAI2 is the least studied of these proteins, with no established role in neuronal or synaptic development. BAI2 also appears to be the most functionally non-redundant member of the BAI family. Though whole exome data from human patients with autism spectrum disorder, schizophrenia, and bipolar disorder suggests all BAI proteins are implicated in these conditions, BAI2 does not bind the same presynaptic proteins as BAI1 and BAI3. Furthermore, a gain-of- function mutation to BAI2 is the putative cause of a rare spastic paraparesis condition in humans, and loss-of- function mutations are associated with hyperactive behavior in mice. Addressing the fundamental role and molecular mechanism of BAI2 thus can help us understand both basic synapse development, and potentially inform future studies into treatments of psychiatric and central nervous system-derived motor disorders. To this end, my data on BAI2 suggests that the protein localizes to the PSD and promotes both pre- and postsynaptic development. I propose to further define the role of BAI2 in synapse and spine development by delineating the functional domains that regulate synapse development (Aim 1.1), quantifying nanostructural changes to synaptic structures (Aim 1.2), and describing functional deficits (Aim 1.3) induced by loss of BAI2. In the future, I plan to pursue a postdoctoral position investigating real-time changes to excitatory and inhibitory synaptic nanodomains and signaling in baseline, plasticity, and disease conditions (Aim 2).