Altered postnatal maturation of electrical properties in spinal motoneurons in a mouse model of amyotrophic lateral sclerosis

Non-technical summary Our focus was on whether amyotrophic lateral sclerosis (ALS) might be precipitated by early developmental changes in large spinal motoneurons, which are vulnerable to early die-off in ALS. It has been shown that some electrical properties in motoneurons are profoundly altered soon after birth in mutant superoxide dismutase-1 (SOD1) mice, a standard animal model of ALS. These same properties undergo rapid developmental changes in normal mice during this time period. Our goal was to compare the development of motoneuron electrical properties in normal and SOD1 mice. Properties were measured from birth to 12 days of age, when the mouse is considered juvenile, but long before symptom onset. Most electrical properties in the SOD1 motoneurons showed an accelerated pace of maturation during this early developmental period compared with the normal motoneurons. If this trend persists, it could, along with other disease factors, hasten the onset of normal motoneuron degeneration due to ageing and result in the development of ALS.Spinal motoneurons are highly vulnerable in amyotrophic lateral sclerosis (ALS). Previous research using a standard animal model, the mutant superoxide dismutase-1 (SOD1) mouse, has revealed deficits in many cellular properties throughout its lifespan. The electrical properties underlying motoneuron excitability are some of the earliest to change; starting at 1 week postnatal, persistent inward currents (PICs) mediated by Na+ are upregulated and electrical conductance, a measure of cell size, increases. However, during this period these properties and many others undergo large developmental changes which have not been fully analysed. Therefore, we undertook a systematic analysis of electrical properties in more than 100 normal and mutant SOD1 motoneurons from 0 to 12 days postnatal, the neonatal to juvenile period. We compared normal mice with the most severe SOD1 model, the G93A high-expressor line. We found that the Na+ PIC and the conductance increased during development. However, mutant SOD1 motoneurons showed much greater increases than normal motoneurons; the mean Na+ PIC in SOD1 motoneurons was double that of wild-type motoneurons. Additionally, in mutant SOD1 motoneurons the PIC mediated by Ca2+ increased, spike width decreased and the time course of the after-spike after-hyperpolarization shortened. These changes were advances of the normal effects of maturation. Thus, our results show that the development of normal and mutant SOD1 motoneurons follows generally similar patterns, but that the rate of development is accelerated in the mutant SOD1 motoneurons. Statistical analysis of all measured properties indicates that approximately 55% of changes attributed to the G93A SOD1 mutation can be attributed to an increased rate of maturation.