LRRTM2 controls presynapse nano-organization and AMPA receptor sub-positioning through Neurexin-binding interface

Synapses are organized into nanocolumns that control neurotransmission efficacy through precise alignment of postsynaptic AMPARs and presynaptic release sites. How these are trans-synaptically arranged remains elusive, despite evidence involving adhesion proteins. Highly enriched and confined at synapses, Leucine-Rich Repeat Transmembrane protein LRRTM2, is ideally poised to play this role by interacting with presynaptic Neurexins. Recent evidence show that LRRTM2 interacts with Neurexins through the C-terminal cap of LRRTM2 extracellular domain, but the role of this binding interface containing E348 has not been explored in synapse formation and function. Here, we developed a conditional knock-out mouse model (cKO) to address these questions and iden-tify LRRTM2 as a critical regulator of synapse nano-organization. We show that LRRTM2 cKO specifically impairs excitatory synapse formation and function. Surface expression, synaptic clustering, and membrane diffusion are tightly controlled by different motifs in LRRTM2 C-terminal domain, while the N-terminal domain controls pre-synapse nano-organization, AMPARs sub-positioning and stabilization, through the recently identified Neurexin-binding interface. Thus, LRRTM2 appears as a central organizer of synapse nanostructure through interaction with presynaptic Neurexins.