Hypoexcitability precedes denervation in the large fast-contracting motor units in two unrelated mouse models of ALS
- CNRS/Université Paris Descartes, France
- Columbia University, United States
- Northwestern University, United States
- 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
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
- 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
- Received: August 4, 2017
- Accepted: March 14, 2018
- Accepted Manuscript published: March 27, 2018 (version 1)
- 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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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
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