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

Su Wei Kuo, Marc D. Binder, C. J. Heckman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article number9049
JournalScientific reports
Issue number1
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • General


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