Embryonic alteration of motoneuronal morphology induces hyperexcitability in the mouse model of amyotrophic lateral sclerosis

Neurobiol Dis. 2013 Jun:54:116-26. doi: 10.1016/j.nbd.2013.02.011. Epub 2013 Mar 4.


Although amyotrophic lateral sclerosis (ALS) is an age-dependent fatal neurodegenerative disease in which upper and lower motoneurons (MNs) are targeted for death in adults, increasing lines of evidence indicate that MNs display physiological and morphological abnormalities during postnatal development, long before disease onset. Here, using transgenic mice overexpressing the G93A mutation of the human Cu/Zn superoxide dismutase gene (SOD1), we show that SOD1(G93A) embryonic lumbar E17.5 MNs already expressed abnormal morphometric parameters, including a deep reduction of their terminal segments length. Whole-cell patch-clamp recordings from acute spinal cord preparations were made to characterize functional changes in neuronal activity. SOD1(G93A) E17.5 MNs displayed hyperexcitability compared to wild-type MNs. Finally, we performed realistic simulations in order to correlate morphometric and electrophysiological changes observed in embryonic SOD1(G93A) MNs. We found that the reduced dendritic elongation mainly accounted for the hyperexcitability observed in SOD1(G93A) MNs. Altogether, our results emphasize the remarkable early onset of abnormal neural activity in the commonly used animal model for ALS, and suggest that embryonic morphological changes are the primary compensatory mechanisms, the physiological adjustments being only secondary to morphological alterations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / embryology*
  • Amyotrophic Lateral Sclerosis / pathology*
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Disease Models, Animal
  • Embryo, Mammalian
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Microscopy, Confocal
  • Motor Neurons / pathology*
  • Motor Neurons / physiology
  • Patch-Clamp Techniques
  • Superoxide Dismutase / genetics


  • Superoxide Dismutase