Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
- University of Massachusetts Medical School, United States
- Mount Sinai Hospital, Canada
- The Rockefeller University, United States
Abstract
Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic- and decreased GABAergic-transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.
Article and author information
Author details
Funding
National Institutes of Health (GM084491)
- Mark J Alkema
National Institutes of Health (NS107475)
- Mei Zhen
- Mark J Alkema
Canadian Institutes of Health Research (154274)
- Mei Zhen
Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-06738)
- Mei Zhen
National Natural Science Foundation of China (31671052)
- Shangbang Gao
National Institutes of Health (NS064263)
- Michael M Francis
Consejo Nacional de Investigaciones Científicas y Técnicas (Postdoctoral fellowship)
- Diego Rayes
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Piali Sengupta, Brandeis University, United States
Version history
- Received: February 18, 2019
- Accepted: July 30, 2019
- Accepted Manuscript published: July 31, 2019 (version 1)
- Accepted Manuscript updated: August 5, 2019 (version 2)
- Version of Record published: August 28, 2019 (version 3)
Copyright
© 2019, Huang et al.
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.
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Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
eLife 8:e45905.
https://doi.org/10.7554/eLife.45905
Further reading
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