Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses

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Abstract

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.

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Quynh-Anh Nguyen

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Meryl E Horn

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Roger A Nicoll

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

For correspondence
roger.nicoll@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6977-4632

Funding

American Heart Association (Predoctoral Fellowship)

Quynh-Anh Nguyen

National Science Foundation (Graduate Research Fellowship)

Meryl E Horn

National Institute of Mental Health

Roger A Nicoll

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All experiments were performed in accordance with established protocols approved by the University of California San Francisco Institutional Animal Care and Use Committee (PHS Assurance #A3400-01).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.