Excessive Homeostatic Gain in Spinal Motoneurons in a Mouse Model of Amyotrophic Lateral Sclerosis

Sci Rep. 2020 Jun 3;10(1):9049. doi: 10.1038/s41598-020-65685-8.


In the mSOD1 model of ALS, the excitability of motoneurons is poorly controlled, oscillating between hyperexcitable and hypoexcitable states during disease progression. The hyperexcitability is mediated by excessive activity of voltage-gated Na+ and Ca2+ channels that is initially counteracted by aberrant increases in cell size and conductance. The balance between these opposing actions collapses, however, at the time that the denervation of muscle fibers begins at about P50, resulting in a state of hypo-excitability and cell death. We propose that this process of neurodegeneration ensues from homeostatic dysregulation of excitability and have tested this hypothesis by perturbing a signal transduction pathway that plays a major role in controlling biogenesis and cell size. Our 『homeostatic dysregulation hypothesis' predicted that neonatal mSOD1 motoneurons would be much more sensitive to such perturbations than wild type controls and our results strongly support this hypothesis. Our results have important implications for therapeutic approaches to ALS.

MeSH terms

  • Action Potentials / physiology
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Disease Models, Animal
  • Female
  • Homeostasis / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Neurons / metabolism
  • Motor Neurons / physiology*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / physiology
  • Signal Transduction / physiology
  • Spinal Cord / metabolism
  • Spinal Cord / physiology*
  • Superoxide Dismutase-1 / metabolism


  • Superoxide Dismutase-1