LRRTM2 Interacts with Neurexin1 and Regulates Excitatory Synapse Formation

Joris de Wit, Emily Sylwestrak, Matthew L. O'Sullivan, Stefanie Otto, Katie Tiglio, Jeffrey N. Savas, John R. Yates, Davide Comoletti, Palmer Taylor, Anirvan Ghosh

Research output: Contribution to journalArticlepeer-review

265 Scopus citations

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 1α and Neurexin 1β, 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.

Original languageEnglish (US)
Pages (from-to)799-806
Number of pages8
JournalNeuron
Volume64
Issue number6
DOIs
StatePublished - Dec 24 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • cellbio
  • molneuro
  • signaling

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