Nerve excitability changes related to axonal degeneration in amyotrophic lateral sclerosis: Insights from the transgenic SOD1(G127X) mouse model

Exp Neurol. 2012 Jan;233(1):408-20. doi: 10.1016/j.expneurol.2011.11.008. Epub 2011 Nov 15.


Motor nerve excitability studies by "threshold tracking" in amyotrophic lateral sclerosis (ALS) revealed heterogeneous abnormalities in motor axon membrane function possibly depending on disease stage. It remains unclear to which extent the excitability deviations reflect a pathogenic mechanism in ALS or are merely a consequence of axonal degeneration. We investigated motor axon excitability in presymptomatic and symptomatic SOD1(G127X) mutants, a mouse model of ALS with late clinical onset and rapid disease progression. After clinical onset, there was a rapid loss of functional motor units associated with an increase in rheobase and strength-duration time constant, an increase in refractoriness at the expense of the superexcitability, larger than normal threshold deviations during both depolarizing and hyperpolarizing threshold electrotonus with impaired accommodation and reduction of the input conductance. These abnormalities progressed rapidly over a few days and were associated with morphological evidence of ongoing axonal degeneration. Presymptomatic mice with unaltered motor performance at rotor-rod measurement also had an increase in refractoriness at the expense of the superexcitability during the recovery cycle. This was, however, associated with smaller than normal deviations during threshold electrotonus, and a steeper resting current-threshold slope indicating slight axonal depolarization in agreement with motoneuronal hyperexcitability indicated by enhanced F-waves. Our data suggest that SOD1(G127X) motor axons undergo a state of membrane depolarization; however, during rapid motoneuron loss disease-specific nerve excitability measures are confounded by excitability changes in degenerating but still conducting axons. These findings should be considered in the interpretation of disease-stage-related nerve excitability changes in ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / complications
  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / pathology
  • Animals
  • Axons / physiology*
  • Differential Threshold
  • Disease Models, Animal
  • Electric Stimulation
  • Electromyography
  • Glycine / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Motor Neurons / physiology*
  • Movement / physiology
  • Neural Conduction / genetics
  • Reaction Time / genetics
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase-1
  • Tibial Nerve / pathology*
  • Time Factors


  • SOD1 protein, human
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Glycine