UC San Diego

Latrophilins (LPHNs) are a small family of orphan G- protein coupled receptors (GPCRs) known to mediate the massive synaptic exocytosis caused by the black widow spider venom [alpha]-latrotoxin, but their endogenous ligands and function remain unclear. Here we identify the FLRT (Fibronectin and Leucine-rich Repeat Transmembrane) family of transmembrane proteins as novel endogenous ligands for latrophilins using affinity chromatography and mass spectrometry. We demonstrate that FLRT3 and LPHN3 ectodomains interact with high affinity in trans. We show that FLRT3 is expressed by specific subpopulations of hippocampal neurons and localizes to postsynaptic sites. Interference with endogenous LPHN complexes using soluble recombinant LPHN3 reduces the density of excitatory synapses in cultured neurons and loss of FLRT3 reduces afferent input strength and synapse number in dentate granule cells in vivo. Our results identify a novel function for the ADHD (Attention Deficit Hyperactivity Disorder)-linked LPHN3 protein in mediating trans-synaptic adhesion with FLRTs and demonstrate that FLRT3 is required for normal synapse development