Calpain fosters the hyperexcitability of motoneurons after spinal cord injury and leads to spasticity

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Abstract

Up-regulation of the persistent sodium current (I_NaP) and down-regulation of the potassium/chloride extruder KCC2 lead to spasticity after spinal cord injury (SCI). We here identified calpain as the driver of the up- and down-regulation of I_NaP andKCC2, respectively, in neonatal rat lumbar motoneurons. Few days after SCI, neonatal rats developed behavioral signs of spasticity with the emergence of both hyperreflexia and abnormal involuntary muscle contractions on hindlimbs. At the same time, in vitro isolated lumbar spinal cords became hyperreflexive and displayed numerous spontaneous motor outputs. Calpain-I expression paralleled with a proteolysis of voltage-gated sodium (Nav) channels and KCC2. Acute inhibition of calpains reduced this proteolysis, restored the motoneuronal expression of Nav and KCC2, normalized I_NaP and KCC2 function, and curtailed spasticity. In sum, by up- and down-regulating I_NaP and KCC2, the calpain-mediated proteolysis of Nav and KCC2 drives the hyperexcitability of motoneurons which leads to spasticity after SCI.

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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all Figures and Supplementary Figures of the manuscript.

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Vanessa Plantier

Institut de Neurosciences de la Timone, CNRS Aix Marseille University, Marseille, France

Competing interests
The authors declare that no competing interests exist.
Irene Sanchez-Brualla

Institut de Neurosciences de la Timone, CNRS Aix Marseille University, Marseille, France

Competing interests
The authors declare that no competing interests exist.
Nejada Dingu

Institut de Neurosciences de la Timone, CNRS Aix Marseille University, Marseille, France

Competing interests
The authors declare that no competing interests exist.
Cécile Brocard

Institut de Neurosciences Timone UMR7289, CNRS Aix Marseille University, Marseille, France

Competing interests
The authors declare that no competing interests exist.
Sylvie Liabeuf

Institut de Neurosciences de la Timone, CNRS Aix Marseille University, Marseille, France

Competing interests
The authors declare that no competing interests exist.
Florian Gackière

Institut de Neurosciences de la Timone, CNRS Aix Marseille University, Marseille, France

Competing interests
The authors declare that no competing interests exist.
Frédéric Brocard

Institut de Neurosciences de la Timone, CNRS Aix Marseille University, Marseille, France

For correspondence
frederic.brocard@univ-amu.fr

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9444-9586

Funding

Agence Nationale de la Recherche (ANR CalpaSCI-16-CE16-0004)

Frédéric Brocard

Institut Recherche sur la Moelle Epiniere (SPV/MB/173439)

Frédéric Brocard

Fondation pour la Recherche Médicale (FDT20170437125)

Frédéric Brocard

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

Ethics

Animal experimentation: We made all efforts to minimize animal suffering and the number of animals used. All animal care and use conformed to the French regulations (Décret 2010-118) and were approved by the local ethics committee (Comité d'Ethique en Neurosciences INT-Marseille, CE Nb A1301404, authorization Nb 2018110819197361).

Copyright

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.