Trans-synaptic interaction of orphan GPCR GPR88 and adhesion GPCR BAI3 through C1ql1 maintains synapse integrity

GPR88 is an orphan GPCR with genetic variants associated with multiple neuropsychiatric conditions. GPR88 exhibits enriched expression in the striatum, olfactory tubercle, and inferior olive. Despite these functional associations, its endogenous ligand and its downstream molecular pathways remain unresolved. Here, we found that climbing fiber (CF)-localized GPR88 regulates CF-Purkinje cell synapses in the cerebellum and associative learning behaviors. The results support the CF-secreted protein C1ql1 as the ligand of GPR88 and further revealed that C1ql1 activates biased Gq signaling to enhance CF synapses. Last, we demonstrated that GPR88 anchors C1ql1 and, via C1ql1, forms a tripartite complex with the postsynaptic adhesion GPCR BAI3 in vitro. These findings resolve the orphan status of GPR88 and likely reveal a mechanism by which a secreted protein links two GPCRs to fine-tune synaptic signaling at pre- and postsynaptic sites.