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
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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.
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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
Publication 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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Further reading
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- Developmental Biology
- Genetics and Genomics
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- Developmental Biology
- Genetics and Genomics
