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

• Published in: Nature communications Vol. 15; no. 1; pp. 8807 - 18
• Main Authors: Liouta, Konstantina, Lubas, Malgorzata, Venugopal, Vasika, Chabbert, Julia, Jeannière, Caroline, Diaz, Candice, Munier, Matthieu, Tessier, Béatrice, Claverol, Stéphane, Favereaux, Alexandre, Sainlos, Matthieu, de Wit, Joris, Letellier, Mathieu, Thoumine, Olivier, Chamma, Ingrid
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/109; 14; 14/34; 14/35; 14/63; 631/378/548; 631/378/87; 82/51; 82/58; 82/80; Alignment; Animals; Binding; Clustering; Hippocampus - metabolism; Humanities and Social Sciences; Interfaces; Leucine; Life Sciences; Male; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Molecular modelling; multidisciplinary; Mutation; Nanostructure; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurosciences; Neurotransmitter receptors; Neurotransmitters; Postsynapse; Presynapse; Protein Binding; Proteins; Receptor mechanisms; Receptors; Receptors, AMPA - chemistry; Receptors, AMPA - metabolism; Science; Science (multidisciplinary); Synapses; Synapses - metabolism; Synaptic clustering; Synaptic transmission; Synaptic Transmission - physiology; Synaptogenesis; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53090-y

Synapses are organized into nanocolumns that control synaptic transmission efficacy through precise alignment of postsynaptic neurotransmitter receptors and presynaptic release sites. Recent evidence show that Leucine-Rich Repeat Transmembrane protein LRRTM2, highly enriched and confined at synapses, interacts with Neurexins through its C-terminal cap, but the role of this binding interface has not been explored in synapse formation and function. Here, we develop a conditional knock-out mouse model (cKO) to address the molecular mechanisms of LRRTM2 regulation, and its role in synapse organization and function. We show that LRRTM2 cKO specifically impairs excitatory synapse formation and function in mice. Surface expression, synaptic clustering, and membrane dynamics of LRRTM2 are tightly controlled by selective motifs in the C-terminal domain. Conversely, the N-terminal domain controls presynapse nano-organization and postsynapse AMPAR sub-positioning and stabilization through the recently identified Neurexin-binding interface. Thus, we identify LRRTM2 as a central organizer of pre- and post- excitatory synapse nanostructure through interaction with presynaptic Neurexins. Synapse nanocolumns control neural transmission through precise alignment of neurotransmitter receptors and release sites. Here, the authors identify the Neurexin-LRRTM2 complex as a central organiser of excitatory synapse nanostructure and function.