The vulnerability of spinal motoneurons and soma size plasticity in a mouse model of amyotrophic lateral sclerosis

Abstract

Alpha-motoneuron soma size is correlated with the cell's excitability and function, and has been posited as a plastic property that changes during cellular maturation, injury, and disease. This study examined whether alpha-motoneuron somas change in size over disease progression in the G93A mouse model of amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motoneuron death. We used 2D- and 3D-morphometric analysis of motoneuron size and measures of cell density at four key disease stages: Neonatal, P10 – with earliest known disease changes; young adult, P30 – presymptomatic with early motoneuron death; symptom onset, P90 – with death of 70–80% of motoneurons; and end-stage, P120+ – with full paralysis of hindlimbs. We additionally examined differences in lumbar vs. sacral vs. cervical motoneurons; in motoneurons from male vs. female mice; and in fast vs. slow motoneurons. We present the first evidence of plastic changes in the soma size of spinal α-motoneurons occurring throughout different stages of ALS with profound effects on motoneuron excitability. Somatic changes are time-dependent and are characterized by early-stage enlargement (P10 and P30); no change around symptom onset; and shrinkage at end-stage. A key finding in the study indicates that disease-vulnerable motoneurons exhibit increased soma sizes (P10 and P30). This pattern was confirmed across spinal cord regions, genders, and motoneuron types. This extends the theory of motoneuron size-based vulnerability in ALS: not only are larger motoneurons more vulnerable to death in ALS, but are also enlarged further in the disease. Such information is valuable for identifying ALS pathogenesis mechanisms.

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