Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis

J Neurosci. 2008 Oct 22;28(43):10864-74. doi: 10.1523/JNEUROSCI.1340-08.2008.


Distinguishing the primary from secondary effects and compensatory mechanisms is of crucial importance in understanding adult-onset neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Transgenic mice that overexpress the G93A mutation of the human Cu-Zn superoxide dismutase 1 gene (hSOD1(G93A) mice) are a commonly used animal model of ALS. Whole-cell patch-clamp recordings from neurons in acute slice preparations from neonatal wild-type and hSOD1(G93A) mice were made to characterize functional changes in neuronal activity. Hypoglossal motoneurons (HMs) in postnatal day 4 (P4)-P10 hSOD1(G93A) mice displayed hyperexcitability, increased persistent Na(+) current (PC(Na)), and enhanced frequency of spontaneous excitatory and inhibitory transmission, compared with wild-type mice. These functional changes in neuronal activity are the earliest yet reported for the hSOD1(G93A) mouse, and are present 2-3 months before motoneuron degeneration and clinical symptoms appear in these mice. Changes in neuronal activity were not restricted to motoneurons: superior colliculus interneurons also displayed hyperexcitability and synaptic changes (P10-P12). Furthermore, in vivo viral-mediated GFP (green fluorescent protein) overexpression in hSOD1(G93A) HMs revealed precocious dendritic remodeling, and behavioral assays revealed transient neonatal neuromotor deficits compared with controls. These findings underscore the widespread and early onset of abnormal neural activity in this mouse model of the adult neurodegenerative disease ALS, and suggest that suppression of PC(Na) and hyperexcitability early in life might be one way to mitigate or prevent cell death in the adult CNS.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / pathology*
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Animals, Newborn
  • Brain Stem / cytology*
  • Disease Models, Animal
  • Dose-Response Relationship, Radiation
  • Electric Stimulation
  • Excitatory Amino Acid Agonists / pharmacology
  • Female
  • Functional Laterality
  • Humans
  • In Vitro Techniques
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Membrane Potentials / radiation effects
  • Mice
  • Mice, Transgenic
  • Nerve Net / pathology
  • Nerve Net / physiopathology*
  • Neural Pathways / cytology
  • Neurons / classification
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Superior Colliculi / cytology*
  • Superoxide Dismutase / genetics
  • gamma-Aminobutyric Acid / pharmacology


  • Excitatory Amino Acid Agonists
  • gamma-Aminobutyric Acid
  • SOD1 G93A protein
  • Superoxide Dismutase