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We here identified calpain as the driver of the up- and down-regulation of INaP and KCC2, 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 INaP and KCC2 function, and curtailed spasticity. In sum, by up- and down-regulating INaP and KCC2, the calpain-mediated proteolysis of Nav and KCC2 drives the hyperexcitability of motoneurons which leads to spasticity after SCI.<\/jats:p>","DOI":"10.7554\/elife.51404","type":"journal-article","created":{"date-parts":[[2019,12,9]],"date-time":"2019-12-09T08:00:24Z","timestamp":1575878424000},"source":"Crossref","is-referenced-by-count":38,"title":["Calpain fosters the hyperexcitability of motoneurons after spinal cord injury and leads to spasticity"],"prefix":"10.7554","volume":"8","author":[{"given":"Vanessa","family":"Plantier","sequence":"first","affiliation":[{"name":"Institut de Neurosciences de la Timone (UMR7289), Aix-Marseille Universit\u00e9 and CNRS, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Sanchez-Brualla","sequence":"additional","affiliation":[{"name":"Institut de Neurosciences de la Timone (UMR7289), Aix-Marseille Universit\u00e9 and CNRS, Marseille, 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