Relaxation of synaptic inhibitory events as a compensatory mechanism in fetal SOD spinal motor networks

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons (MNs) during late adulthood. Here, with the aim of identifying early changes underpinning ALS neurodegeneration, we analyzed the GABAergic/glycinergic inputs to E17.5 fetal MNs from SOD1G93A (SOD) mice in parallel with chloride homeostasis. Our results show that IPSCs are less frequent in SOD animals in accordance with a reduction of synaptic VIAAT-positive terminals. SOD MNs exhibited an EGABAAR 10 mV more depolarized than in WT MNs associated with a KCC2 reduction. Interestingly, SOD GABAergic/glycinergic IPSCs and evoked GABAAR-currents exhibited a slower decay correlated to elevated [Cl-]i. Computer simulations revealed that a slower relaxation of synaptic inhibitory events acts as compensatory mechanism to strengthen GABA/glycine inhibition when EGABAAR is more depolarized. How such mechanisms evolve during pathophysiological processes remain to be determined, but our data indicate that at least SOD1 familial ALS may be considered as a neurodevelopmental disease.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Pascal Branchereau

    Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA) - UMR 5287, Université de Bordeaux, CNRS, Bordeaux, France
    For correspondence
    pascal.branchereau@u-bordeaux.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3972-8229
  2. Elodie Martin

    Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA) - UMR 5287, Université de Bordeaux, CNRS, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Laura Supiot

    Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA) - UMR 5287, Université de Bordeaux, CNRS, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Fara Hodeib

    Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA) - UMR 5287, Université de Bordeaux, CNRS, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Amandine Laupénie

    Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA) - UMR 5287, Université de Bordeaux, CNRS, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Urvashi Dalvi

    Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA) - UMR 5287, Université de Bordeaux, CNRS, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Hongmei Zhu

    Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA) - UMR 5287, Université de Bordeaux, CNRS, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  8. William Cazenave

    Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA) - UMR 5287, Université de Bordeaux, CNRS, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Daniel Cattaert

    Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA) - UMR 5287, Université de Bordeaux, CNRS, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.

Funding

Federation pour la Recherche sur le Cerveau

  • Pascal Branchereau

Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone

  • Pascal Branchereau

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

Reviewing Editor

  1. Inna Slutsky, Tel Aviv University, Israel

Ethics

Animal experimentation: All procedures were carried out in accordance with the local ethics committee of the University of Bordeaux (Saisine SOD1G093A - APAFiS #19366) and European Committee Council directives. All efforts were made to minimize animal suffering and reduce the number of animals used.

Version history

  1. Received: August 27, 2019
  2. Accepted: December 20, 2019
  3. Accepted Manuscript published: December 23, 2019 (version 1)
  4. Version of Record published: January 21, 2020 (version 2)
  5. Version of Record updated: January 29, 2020 (version 3)
  6. Version of Record updated: January 29, 2020 (version 4)
  7. Version of Record updated: March 24, 2023 (version 5)

Copyright

© 2019, Branchereau 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. Pascal Branchereau
  2. Elodie Martin
  3. Laura Supiot
  4. Fara Hodeib
  5. Amandine Laupénie
  6. Urvashi Dalvi
  7. Hongmei Zhu
  8. William Cazenave
  9. Daniel Cattaert
(2019)
Relaxation of synaptic inhibitory events as a compensatory mechanism in fetal SOD spinal motor networks
eLife 8:e51402.
https://doi.org/10.7554/eLife.51402

Share this article

https://doi.org/10.7554/eLife.51402

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