LRRTM2 Interacts with Neurexin1 and Regulates Excitatory Synapse Formation

• DOI: 10.1016/j.neuron.2009.12.019
• Publication Date: 2009-12-24T09:10:32Z
• Authors: Joris de Wit; Emily Sylwestrak; Matthew L. O'Sull...; Stefanie Otto; Katie Tiglio; Jeffrey N. Savas; John R. Yates; Davide Comoletti; Palmer Taylor; Anirvan Ghosh
• Keywords: 0301 basic medicine; Neuroscience(all); Receptors, Cell Surface; Hippocampus; 03 medical and health sciences; Organ Culture Techniques; Neural Pathways; Animals; Receptors, AMPA; Neural Cell Adhesion Molecules; cellbio; Calcium-Binding Proteins; Intracellular Signaling Peptides and Proteins; Excitatory Postsynaptic Potentials; Gene Expression Regulation, Developmental; Membrane Proteins; Cell Differentiation; Protein Structure, Tertiary; Rats; molneuro; Synapses; RNA Interference; signaling; Disks Large Homolog 4 Protein; Protein Binding; Signal Transduction

We identify the leucine-rich repeat transmembrane protein LRRTM2 as a key regulator of excitatory synapse development and function. LRRTM2 localizes to excitatory synapses in transfected hippocampal neurons, and shRNA-mediated knockdown of LRRTM2 leads to a decrease in excitatory synapses without affecting inhibitory synapses. LRRTM2 interacts with PSD-95 and regulates surface expression of AMPA receptors, and lentivirus-mediated knockdown of LRRTM2 in vivo decreases the strength of evoked excitatory synaptic currents. Structure-function studies indicate that LRRTM2 induces presynaptic differentiation via the extracellular LRR domain. We identify Neurexin1 as a receptor for LRRTM2 based on affinity chromatography. LRRTM2 binds to both Neurexin 1alpha and Neurexin 1beta, and shRNA-mediated knockdown of Neurexin1 abrogates LRRTM2-induced presynaptic differentiation. These observations indicate that an LRRTM2-Neurexin1 interaction plays a critical role in regulating excitatory synapse development.