Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses.
Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses. These domains point to a gephyrin-dependent mechanism that is disrupted by an autism-associated mutation at R705 and a gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Our work highlights unique and separate roles for the extracellular and intracellular regions in specifying and carrying out NLGN function respectively.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.|Neuroscience Graduate Program, University of California, San Francisco, San Francisco, United States.
Quynh-Anh
QA
Nguyen
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.|Neuroscience Graduate Program, University of California, San Francisco, San Francisco, United States.
Meryl E
ME
Horn
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.|Department of Physiology, University of California, San Francisco, San Francisco, United States.
Roger A
0000-0002-6977-4632
RA
Nicoll
D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000473:pathology; D051381:Rats; D013569:Synapses / Q000378:metabolism
D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C073441:gephyrin; C098003:neuroligin 2; C098004:neuroligin 3
autism; gephyrin; inhibitory synapse; neuroligin 2; neuroligin 3; neuroligins; neuroscience; rat