Latrophilin GPCRs direct synapse specificity by coincident binding of FLRTs and teneurins

Abstract

Coincidence detection in synaptogenesis In the brain, synaptic connections are formed with exquisite specificity, but the underlying molecular mechanisms remain largely unexplored. Synapse formation is thought to involve bidirectional signaling by proteins that bind to each other across the synaptic cleft. Sando et al. used conditional genetic tools and in vitro assays to investigate the mechanisms of synapse formation. They found that synapse formation in the mouse hippocampus requires latrophilins. Latrophilins are G protein–coupled receptors that bind to cell-surface proteins called teneurins and fibronectin leucine-rich repeat transmembrane proteins (FLRTs). Two different latrophilins mediated formation of distinct synapses on the same hippocampal neuron. This function required binding of both teneurins and FLRTs. Thus, latrophilins may guide synapse formation by coincidence signaling, which could help to explain the specificity of synaptic connections. Science , this issue p. eaav7969