Hyperexcitability of Cultured Spinal Motoneurons from Presymptomatic ALS Mice

Jason J. Kuo, Martijn Schonewille, Teepu Siddique, Annet N A Schults, Ronggen Fu, Peter R. Bär, Roberta Anelli, C. J. Heckman, Alfons B A Kroese*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

131 Scopus citations


ALS (amyotrophic lateral sclerosis) is an adult-onset and deadly neurodegenerative disease characterized by a progressive and selective loss of motoneurons. Transgenic mice overexpressing a mutated human gene (G93A) coding for the enzyme SOD1 (Cu/Zn superoxide dismutase) develop a motoneuron disease resembling ALS in humans. In this generally accepted ALS model, we tested the electrophysiological properties of individual embryonic and neonatal spinal motoneurons in culture by measuring a wide range of electrical properties influencing motoneuron excitability during current clamp. There were no differences in the motoneuron resting potential, input conductance, action potential shape, or afterhyperpolarization between G93A and control motoneurons. The relationship between the motoneuron's firing frequency and injected current (f-I relation) was altered. The slope of the f-I relation and the maximal firing rate of the G93A motoneurons were much greater than in the control motoneurons, Differences in spontaneous synaptic input were excluded as a cause of increased excitability. This finding identifies a markedly elevated intrinsic electrical excitability in cultured embryonic and neonatal mutant G93A spinal motoneurons. We conclude that the observed intrinsic motoneuron hyperexcitability is induced by the SOD I toxic gain-of-function through an aberration in the process of action potential generation. This hyperexcitability may play a crucial role in the pathogenesis of ALS as the motoneurons were cultured from presymptomatic mice.

Original languageEnglish (US)
Pages (from-to)571-575
Number of pages5
JournalJournal of neurophysiology
Issue number1
StatePublished - Jan 2004

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology


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