BAI Adhesion-GPCRs: Key Regulators of Synapse Development and Plasticity in Health and Disease

PROJECT SUMMARY/ABSTRACT Development fashions 1011 neurons in the brain that form 1014 tightly regulated synaptic connections which un- derlie cognition and emotion. Numerous neuropsychiatric diseases arise from even small genetic perturbations or environmental insults affecting synapse development, including autism spectrum disorder (ASD), schizo- phrenia, bipolar disorder, depression, and intellectual disability. Adhesion G protein-coupled receptors (A- GPCRs) are the second largest and least understood GPCR family. They play critical roles in brain development and function and are increasingly linked to human disease, lending urgency to their study, especially given their untapped potential as therapeutic targets. A-GPCRs are characterized by an extracellular N-terminal fragment (NTF) containing multiple adhesion domains, a GPCR autoproteolysis-inducing (GAIN) domain, and a C-terminal fragment (CTF) that includes a 7-transmembrane GPCR domain and an intracellular tail. Most A-GPCRs undergo GAIN-mediated autoproteolytic cleavage, resulting in non-covalently associated NTF/CTF hetero- dimers. In the last decade, autoagonistic ‘Stachel sequences’ were discovered just C-terminal to the GAIN cut sites, giving rise to a ‘canonical’ A-GPCR activation model, in which ligand binding causes NTF/CTF dissociation, unveiling Stachel, which binds and activates the GPCR. However, this model does not apply to all A-GPCR signaling, because A-GPCRs have additional signal domains, and GAIN cleavage, Stachel activation, and GPCR signaling may or may not be utilized in a given A-GPCR signal. We study the BAI A-GPCR subfamily (BAI1-3), whose members are expressed throughout the brain and regulate a growing list of neuronal processes, including excitatory synaptogenesis, synaptic plasticity, and axon/dendrite growth. In this proposal, we will test the contri- butions of BAIs, particularly BAI1, to diverse aspects of excitatory synapse regulation, including (1) presynaptic development and function, (2) postsynaptic stabilization and plasticity, and (3) activity-dependent refinement of hippocampal synapses in brain circuits important for learning and memory. For each process, we will elucidate BAI1’s mechanism of action to test our hypothesis that BAIs sense specific cellular and molecular cues and relay this information to distinct Rho GTPase signaling pathways, thereby directing different facets of synaptic development and function independently. As other A-GPCR subfamilies exhibit functional clustering, we will also consider the roles of BAI2 and 3 in these processes to test whether this is a common feature of A-GPCRs. This proposal tackles complex signaling pathways to answer basic questions of A-GPCR biology, reveal key mechanisms of neurodevelopment and function, and build a framework for testing the potential of BAIs (and other A-GPCRs) as therapeutic targets by illuminating how they can be targeted to manipulate specific processes among the many they govern. As BAIs are implicated in ASD, schizophrenia, bipolar disorder, cognitive ability, mood regulation, and brain cancer, our results could advance understanding of these disorders.