1. Genetics and Genomics
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Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans

  1. Yung-Chi Huang
  2. Jennifer K Pirri
  3. Diego Rayes
  4. Shangbang Gao
  5. Ben Mulcahy
  6. Jeff Grant
  7. Yasunori Saheki
  8. Michael M Francis
  9. Mei Zhen
  10. Mark J Alkema  Is a corresponding author
  1. University of Massachusetts Medical School, United States
  2. Mount Sinai Hospital, Canada
  3. The Rockefeller University, United States
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Cite this article as: eLife 2019;8:e45905 doi: 10.7554/eLife.45905

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.

Article and author information

Author details

  1. Yung-Chi Huang

    Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jennifer K Pirri

    Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Diego Rayes

    Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shangbang Gao

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5431-4628
  5. Ben Mulcahy

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3336-245X
  6. Jeff Grant

    Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yasunori Saheki

    Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Michael M Francis

    Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8076-6668
  9. Mei Zhen

    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0086-9622
  10. Mark J Alkema

    Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    mark.alkema@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1311-5179

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

  1. Piali Sengupta, Brandeis University, United States

Publication history

  1. Received: February 18, 2019
  2. Accepted: July 30, 2019
  3. Accepted Manuscript published: July 31, 2019 (version 1)
  4. Accepted Manuscript updated: August 5, 2019 (version 2)

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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