LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation.
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.
de Wit
Joris
J
Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Sylwestrak
Emily
E
O'Sullivan
Matthew L
ML
Otto
Stefanie
S
Tiglio
Katie
K
Savas
Jeffrey N
JN
Yates
John R
JR
Comoletti
Davide
D
Taylor
Palmer
P
Ghosh
Anirvan
A
D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000502:physiology; D000076122:Disks Large Homolog 4 Protein; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006624:Hippocampus / Q000196:embryology* / Q000378:metabolism* / Q000648:ultrastructure; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009434:Neural Pathways / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D009924:Organ Culture Techniques; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure
D002135:Calcium-Binding Proteins; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; C547192:LRRTM2 protein, rat; D008565:Membrane Proteins; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; C547193:Nrxn1 protein, rat; D018091:Receptors, AMPA; D011956:Receptors, Cell Surface