TY - JOUR TI - Latrophilin GPCR signaling mediates synapse formation AU - Sando, Richard AU - Südhof, Thomas C A2 - Davis, Graeme W A2 - Westbrook, Gary L A2 - Davis, Graeme W VL - 10 PY - 2021 DA - 2021/03/01 SP - e65717 C1 - eLife 2021;10:e65717 DO - 10.7554/eLife.65717 UR - https://doi.org/10.7554/eLife.65717 AB - Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In mouse CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway. KW - synapse formation KW - synapse specificity KW - hippocampus JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -