Release-dependent feedback inhibition by a presynaptically localized ligand-gated anion channel

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Abstract

Presynaptic ligand-gated ion channels (LGICs) have long been proposed to affect neurotransmitter release and to tune neural circuit activity. However, the understanding of their in vivo physiological action remains limited, partly due to the complexity in channel types and scarcity of genetic models. Here we report that C. elegans LGC-46, a member of the Cys-loop acetylcholine (ACh)-gated chloride (ACC) channel family, localizes to presynaptic terminals of cholinergic motor neurons and regulates synaptic vesicle (SV) release kinetics upon evoked release of acetylcholine. Loss of lgc-46 prolongs evoked release, without altering spontaneous activity. Conversely, a gain-of-function mutation of lgc-46 shortens evoked release to reduce synaptic transmission. This inhibition of presynaptic release requires the anion selectivity of LGC-46, and can ameliorate cholinergic over-excitation in a C. elegans model of excitation-inhibition imbalance. These data demonstrate a novel mechanism of presynaptic negative feedback in which an anion-selective LGIC acts as an auto-receptor to inhibit SV release.

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Seika Takayanagi-Kiya

Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Keming Zhou

Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Yishi Jin

Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States

For correspondence
yijin@ucsd.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9371-9860

Funding

National Institutes of Health (R01, 035546)

Yishi Jin

Howard Hughes Medical Institute (Yishi Jin)

Yishi Jin

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

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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.