It has long been suggested that hyperexcitability of motoneurons induces excitotoxicity in Amyotrophic Lateral Sclerosis. However this assumption had received little support so far. In my talk, I will review recent data that we have obtained in our laboratory. We have studied the properties of spinal motoneurons in ALS mouse models: first in adult animals, using an in vivo preparation that we have recently developed and which allows us to perform intracellular recordings of type-identified motoneurons; and then in neonatal animals, using whole cell-recordings of motoneurons in lumbar slices. Our data indicate that intrinsic hyperexcitability is confined to neonatal S-type motoneurons, which are resistant inALS. In sharp contrast FF and FR types motoneurons that degenerate in ALS tend to become hypoexcitable in adults in the days that precede their degeneration. Our results show that, as far as intrinsic hyperexcitability is concerned, it is unlikely to trigger motoneuron degeneration. However, firing does not depend solely on intrinsic properties but also on the synaptic inputs received by the cell. Indeed, motoneuron excitotoxicity might still arise, if a strong unbalance of excitatory versus inhibitory inputs exists in ALS mice. An unbalance towards more excitation could overcome the intrinsic hypoexcitability of vulnerable motoneurons and force them to discharge more than usual. In this perspective, I will also present preliminary experiments in which we have started investigating whether excitatory and inhibitory pathways to motoneurons are dysfunctional or not in ALS.
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