LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation

Neuron. 2009 Dec 24;64(6):799-806. doi: 10.1016/j.neuron.2009.12.019.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins
  • Cell Differentiation / physiology
  • Disks Large Homolog 4 Protein
  • Excitatory Postsynaptic Potentials / genetics
  • Gene Expression Regulation, Developmental / genetics
  • Hippocampus / embryology*
  • Hippocampus / metabolism*
  • Hippocampus / ultrastructure
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Neural Cell Adhesion Molecules / genetics
  • Neural Cell Adhesion Molecules / metabolism*
  • Neural Pathways / embryology
  • Neural Pathways / metabolism
  • Neural Pathways / ultrastructure
  • Organ Culture Techniques
  • Protein Binding / physiology
  • Protein Structure, Tertiary / physiology
  • RNA Interference
  • Rats
  • Receptors, AMPA / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction / genetics
  • Synapses / metabolism*
  • Synapses / ultrastructure
  • Synaptic Membranes / genetics
  • Synaptic Membranes / metabolism
  • Synaptic Membranes / ultrastructure

Substances

  • Calcium-Binding Proteins
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • LRRTM2 protein, rat
  • Membrane Proteins
  • Neural Cell Adhesion Molecules
  • Nrxn1 protein, mouse
  • Nrxn1 protein, rat
  • Receptors, AMPA
  • Receptors, Cell Surface