Extended riluzole treatment paradoxically increases motoneuron excitability in ALS

Abstract Riluzole is the most commonly prescribed among the few approved therapies for amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motoneuron degeneration and paralysis. Although believed to counteract excitotoxicity by suppressing motoneuron excitability and glutamate release, clinical studies show these effects diminish within weeks. Yet, riluzole still yields a modest but measurable survival benefit, raising the question of additional therapeutic mechanisms. We previously showed that homeostatic mechanisms in the SOD1 G93A (mSOD1) mouse model of ALS are hyperactive and prone to overcompensation. Here, we tested whether such dysregulated homeostasis antagonizes the effects of riluzole. Wild-type (WT) and presymptomatic mSOD1 mice received therapeutic doses of riluzole in drinking water for 10 days, with untreated littermates of both genotypes serving as controls. Motoneuron excitability and synaptic inputs were then examined using intracellular recordings from the isolated sacral spinal cord. The data showed that extended riluzole treatment increased motoneuron excitability and polysynaptic inputs in mSOD1 mice but produced no detectable changes in WT motoneurons. These results are consistent with compensatory homeostatic adaptations in ALS counteracting the suppressive effects of riluzole. Notably, mSOD1 motoneurons exhibited larger membrane capacitance than WT, in line with their increased cell size at this disease stage. Riluzole treatment reduced motoneuron membrane capacitance in mSOD1 mice to the range observed in WT animals, suggesting a potential reduction in cell size. The functional significance of this size change remains uncertain. Together, our findings provide new insight into ALS pathology and demonstrates that dysregulated homeostasis can shape therapeutic responses in ALS.