1. Neuroscience
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The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons

  1. Tyne W Miller-Fleming
  2. Sarah C Petersen
  3. Laura Manning
  4. Cristina Matthewman
  5. Megan Gornet
  6. Allison Beers
  7. Sayaka Hori
  8. Shohei Mitani
  9. Laura Bianchi
  10. Janet Richmond
  11. David M Miller III  Is a corresponding author
  1. Vanderbilt University, United States
  2. Kenyon College, United States
  3. University of Illinois at Chicago, United States
  4. University of Miami, United States
  5. Tokyo Women's Medical University, Japan
Research Article
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Cite this article as: eLife 2016;5:e14599 doi: 10.7554/eLife.14599

Abstract

Genetic programming and neural activity drive synaptic remodeling in developing neural circuits, but the molecular components that link these pathways are poorly understood. Here we show that the C. elegans Degenerin/Epithelial Sodium Channel (DEG/ENaC) protein, UNC-8, is transcriptionally controlled to function as a trigger in an activity-dependent mechanism that removes synapses in remodeling GABAergic neurons. UNC-8 cation channel activity promotes disassembly of presynaptic domains in DD type GABA neurons, but not in VD class GABA neurons where unc-8 expression is blocked by the COUP/TF transcription factor, UNC-55. We propose that the depolarizing effect of UNC-8-dependent sodium import elevates intracellular calcium in a positive feedback loop involving the voltage-gated calcium channel UNC-2 and the calcium-activated phosphatase TAX-6/calcineurin to initiate a caspase-dependent mechanism that disassembles the presynaptic apparatus. Thus, UNC-8 serves as a link between genetic and activity-dependent pathways that function together to promote the elimination of GABA synapses in remodeling neurons.

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Author details

  1. Tyne W Miller-Fleming

    Neuroscience Program, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Sarah C Petersen

    Department of Neuroscien, Kenyon College, Gambier, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Laura Manning

    Department of Biological Sciences, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1597-0600

  4. Cristina Matthewman

    Department of Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Megan Gornet

    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Allison Beers

    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Sayaka Hori

    Department of Physiology, Tokyo Women's Medical University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  8. Shohei Mitani

    Department of Physiology, Tokyo Women's Medical University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  9. Laura Bianchi

    Department of Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Janet Richmond

    Department of Biological Sciences, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. David M Miller III

    Neuroscience Program, Vanderbilt University, Nashville, United States
    For correspondence
    david.miller@vanderbilt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9048-873X

Reviewing Editor

  1. Kang Shen, Howard Hughes Medical Institute, Stanford University, United States

Publication history

  1. Received: January 21, 2016
  2. Accepted: July 11, 2016
  3. Accepted Manuscript published: July 12, 2016 (version 1)
  4. Version of Record published: August 10, 2016 (version 2)
  5. Version of Record updated: August 4, 2017 (version 3)

Copyright

© 2016, Miller-Fleming 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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