Thivaios_2026_Nat.Commun_17_

Synapses, prototypic sites for neuronal communication, are key to brain function. Their organization and properties are instructed by synaptic cell adhesion molecules (sCAMs) that may operate independently or in coordination through yet unknown linker proteins. Here, we used multi-epitope affinity-purifications combined with quantitative mass spectrometry and immuno-EM to comprehensively map synaptic protein networks in the mouse brain. We identify a pre-synaptic core-module assembled from the major sCAMs, Neurexins1-3 and LAR-type receptor protein-tyrosine-phosphatases (PTPRs), and the previously uncharacterized tetraspanins T178A/B. These ternary Neurexin-T178-PTPR complexes form through their trans-membrane domains and assemble during biogenesis in the ER. Loss of T178B leads to module destabilization, accompanied by strong reduction of LAR-PTPRs and re-distribution of synaptic Neurexins. At synapses, the Neurexin-T178-PTPR module recruits stable trans-synaptic protein networks thereby interlinking machineries of the pre-synaptic active zone and establishing stable associations with post-synaptic neurotransmitter receptors. This work uncovers a widely distributed core-module for synaptic adhesion and trans-synaptic signaling in the mammalian brain.