Hypoexcitability precedes denervation in the large fast-contracting motor units in two unrelated mouse models of ALS

  1. Maria de Lourdes Martinez-Silva
  2. Rebecca D Imhoff-Manuel
  3. Aarti Sharma
  4. CJ Heckman
  5. Neil A Shneider
  6. Francesco Roselli
  7. Daniel Zytnicki
  8. Marin Manuel  Is a corresponding author
  1. CNRS/Université Paris Descartes, France
  2. Columbia University, United States
  3. Northwestern University, United States
  4. Ulm University, Germany

Abstract

Hyperexcitability has been suggested to contribute to motoneuron degeneration in amyotrophic lateral sclerosis (ALS). If this is so, and given that the physiological type of a motor unit determines the relative susceptibility of its motoneuron in ALS, then one would expect the most vulnerable motoneurons to display the strongest hyperexcitability prior to their degeneration, whereas the less vulnerable should display a moderate hyperexcitability, if any. We tested this hypothesis in vivo in two unrelated ALS mouse models by correlating the electrical properties of motoneurons with their physiological types, identified based on their motor unit contractile properties. We found that, far from being hyperexcitable, the most vulnerable motoneurons become unable to fire repetitively despite the fact that their neuromuscular junctions were still functional. Disease markers confirm that this loss of function is an early sign of degeneration. Our results indicate that intrinsic hyperexcitability is unlikely to be the cause of motoneuron degeneration.

Article and author information

Author details

  1. Maria de Lourdes Martinez-Silva

    Centre de Neurophysique, Physiologie et Pathologie, UMR 8119, CNRS/Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Rebecca D Imhoff-Manuel

    Centre de Neurophysique, Physiologie et Pathologie, UMR 8119, CNRS/Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Aarti Sharma

    Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. CJ Heckman

    Department of Physiology, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Neil A Shneider

    Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3223-7366
  6. Francesco Roselli

    Department of Neurology, Ulm University, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniel Zytnicki

    Centre de Neurophysique, Physiologie et Pathologie, UMR 8119, CNRS/Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0431-9604
  8. Marin Manuel

    Centre de Neurophysique, Physiologie et Pathologie, UMR 8119, CNRS/Université Paris Descartes, Paris, France
    For correspondence
    marin.manuel@neurobio.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5344-3572

Funding

National Institute of Neurological Disorders and Stroke (R01NS077863)

  • CJ Heckman
  • Marin Manuel

Target ALS

  • Aarti Sharma
  • Neil A Shneider
  • Daniel Zytnicki
  • Marin Manuel

AFM-Téléthon (HYPERTOXIC)

  • Daniel Zytnicki
  • Marin Manuel

Synapsis Foundation

  • Francesco Roselli

Baustein Program of Ulm University Medical Faculty

  • Francesco Roselli

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

Reviewing Editor

  1. Lee L Rubin, Harvard Stem Cell Institute, Harvard University, United States

Ethics

Animal experimentation: All experiments were performed in accordance with European directives (86/609/CEE and 2010-63-UE) and the French legislation. They were approved by Paris Descartes University ethics committee (authorizations CEEA34.MM.064.12 and 01256.02). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Version history

  1. Received: August 4, 2017
  2. Accepted: March 14, 2018
  3. Accepted Manuscript published: March 27, 2018 (version 1)
  4. Version of Record published: April 27, 2018 (version 2)

Copyright

© 2018, Martinez-Silva 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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  1. Maria de Lourdes Martinez-Silva
  2. Rebecca D Imhoff-Manuel
  3. Aarti Sharma
  4. CJ Heckman
  5. Neil A Shneider
  6. Francesco Roselli
  7. Daniel Zytnicki
  8. Marin Manuel
(2018)
Hypoexcitability precedes denervation in the large fast-contracting motor units in two unrelated mouse models of ALS
eLife 7:e30955.
https://doi.org/10.7554/eLife.30955

Share this article

https://doi.org/10.7554/eLife.30955

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