Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis

Elife. 2014 Oct 14;3:e04046. doi: 10.7554/eLife.04046.

Abstract

In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow-contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration.

Keywords: ALS; hyperexcitability; motoneuron; mouse; neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Biomarkers / metabolism
  • DNA-Binding Proteins
  • Dendrites / metabolism
  • Disease Models, Animal
  • Matrix Metalloproteinase 9 / metabolism
  • Mice, Transgenic
  • Motor Neurons / pathology*
  • Motor Neurons / physiology
  • Mutation / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / physiopathology*
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Estrogen / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Vesicular Glutamate Transport Protein 1 / metabolism

Substances

  • Biomarkers
  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • NeuN protein, mouse
  • Nuclear Proteins
  • RNA, Messenger
  • Receptors, Estrogen
  • Slc17a7 protein, mouse
  • Vesicular Glutamate Transport Protein 1
  • estrogen receptor-related receptor beta
  • Superoxide Dismutase
  • Matrix Metalloproteinase 9