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.