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Differential effects on KCC2 expression and spasticity of ALS and traumatic injuries to motoneurons

Differential effects on KCC2 expression and spasticity of ALS and traumatic injuries to motoneurons
Differential effects on KCC2 expression and spasticity of ALS and traumatic injuries to motoneurons
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease manifested by progressive muscle atrophy and paralysis due to the loss of upper and lower motoneurons (MN). Spasticity appears in ALS patients leading to further disabling consequences. Loss of the inhibitory tone induced by downregulation of the potassium chloride cotransporter 2 (KCC2) in MN has been proposed to importantly contribute to the spastic behavior after spinal cord injury (SCI). The aim of the present study was to test whether the alterations in the expression of KCC2 are linked to the appearance of spasticity in the SOD(G93A) ALS murine model. We compared SOD(G93A) mice to wild type mice subjected to SCI to mimic the spinal MN disconnection from motor descending pathways, and to sciatic nerve lesion to mimic the loss of MN connectivity to muscle. Electrophysiological results show that loss of motor function is observed at presymptomatic stage (8 weeks) in SOD(G93A) mice but hyperreflexia and spasticity do not appear until a late stage (16 weeks). However, KCC2 was not downregulated despite MN suffered disconnection both from muscles and upper MNs. Further experiments revealed decreased gephyrin expression, as a general marker of inhibitory systems, accompanied by a reduction in the number of Renshaw interneurons. Moreover, 5-HT fibers were increased in the ventral horn of the lumbar spinal cord at late stage of disease progression in SOD1(G93A) mice. Taken together, the present results indicate that spasticity appears late in the ALS model, and may be mediated by a decrease in inhibitory interneurons and an increase of 5-HT transmission, while the absence of down-regulation of KCC2 could rather indicate an inability of MNs to respond to insults
1662-5102
1-11
Mòdol, Laura
b2aea2a0-d11d-4000-9520-65dab58afac7
Mancuso, Renzo
05786562-a993-4e37-926e-3c1fcf50b36d
Alé, Albert
5f0e2ae7-6c81-4dea-a094-bf69cdc094b9
Francos-Quijorna, Isaac
a6f10a12-1236-4f45-ad01-d3f83a21ba1c
Navarro, Xavier
8854ebaa-d283-4d46-829e-c7c8f186585e
Mòdol, Laura
b2aea2a0-d11d-4000-9520-65dab58afac7
Mancuso, Renzo
05786562-a993-4e37-926e-3c1fcf50b36d
Alé, Albert
5f0e2ae7-6c81-4dea-a094-bf69cdc094b9
Francos-Quijorna, Isaac
a6f10a12-1236-4f45-ad01-d3f83a21ba1c
Navarro, Xavier
8854ebaa-d283-4d46-829e-c7c8f186585e

Mòdol, Laura, Mancuso, Renzo, Alé, Albert, Francos-Quijorna, Isaac and Navarro, Xavier (2014) Differential effects on KCC2 expression and spasticity of ALS and traumatic injuries to motoneurons. Frontiers in Cellular Neuroscience, 8, 1-11. (doi:10.3389/fncel.2014.00007). (PMID:24478630)

Record type: Article

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease manifested by progressive muscle atrophy and paralysis due to the loss of upper and lower motoneurons (MN). Spasticity appears in ALS patients leading to further disabling consequences. Loss of the inhibitory tone induced by downregulation of the potassium chloride cotransporter 2 (KCC2) in MN has been proposed to importantly contribute to the spastic behavior after spinal cord injury (SCI). The aim of the present study was to test whether the alterations in the expression of KCC2 are linked to the appearance of spasticity in the SOD(G93A) ALS murine model. We compared SOD(G93A) mice to wild type mice subjected to SCI to mimic the spinal MN disconnection from motor descending pathways, and to sciatic nerve lesion to mimic the loss of MN connectivity to muscle. Electrophysiological results show that loss of motor function is observed at presymptomatic stage (8 weeks) in SOD(G93A) mice but hyperreflexia and spasticity do not appear until a late stage (16 weeks). However, KCC2 was not downregulated despite MN suffered disconnection both from muscles and upper MNs. Further experiments revealed decreased gephyrin expression, as a general marker of inhibitory systems, accompanied by a reduction in the number of Renshaw interneurons. Moreover, 5-HT fibers were increased in the ventral horn of the lumbar spinal cord at late stage of disease progression in SOD1(G93A) mice. Taken together, the present results indicate that spasticity appears late in the ALS model, and may be mediated by a decrease in inhibitory interneurons and an increase of 5-HT transmission, while the absence of down-regulation of KCC2 could rather indicate an inability of MNs to respond to insults

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Accepted/In Press date: 6 January 2014
Published date: 24 January 2014
Organisations: Centre for Biological Sciences

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Local EPrints ID: 376144
URI: http://eprints.soton.ac.uk/id/eprint/376144
ISSN: 1662-5102
PURE UUID: 8e52860a-55f9-4823-85c8-3c4eaa2ef286

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Date deposited: 27 Apr 2015 10:40
Last modified: 19 Jul 2019 20:47

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Author: Laura Mòdol
Author: Renzo Mancuso
Author: Albert Alé
Author: Isaac Francos-Quijorna
Author: Xavier Navarro

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