Time course of alterations in adult spinal motoneuron properties in the SOD1(G93A) mouse model of ALS

Abstract Although ALS is an adult-onset neurodegenerative disease, motoneuron electrical properties are already altered during embryonic development. Motoneurons must therefore exhibit a remarkable capacity for homeostatic regulation to maintain a normal motor output for most of the life of the patient. In the present paper, we demonstrate how maintaining homeostasis could come at a very high cost. We studied the excitability of spinal motoneurons from young adult SOD1(G93A) mice to end-stage. Initially homeostasis is highly successful in maintaining their overall excitability. This initial success, however, is achieved by pushing some cells far above the normal range of passive and active conductances. As the disease progresses, both passive and active conductances shrink below normal values in the surviving cells. This shrinkage may thus promote survival, implying the previously large values contribute to degeneration. These results support the hypothesis that motoneuronal homeostasis may be “hyper-vigilant” in ALS and a source of accumulating stress. Significance StatementDuring ALS, motoneurons exhibit a remarkable ability to maintain a normal motor output despite continuous alterations of their electrophysiological properties, up to the point when overt symptoms become apparent. We show that this homeostatic process can sometimes push motoneurons beyond the normal range, which may be causing long-lasting harm.