Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis

Exp Neurol. 2009 Feb;215(2):368-79. doi: 10.1016/j.expneurol.2008.11.002. Epub 2008 Nov 21.


Cortical hyperexcitability has been observed in Amyotrophic Lateral Sclerosis (ALS) patients. Familial ALS accounts for 10% of all cases and mutations of the Cu,Zn superoxide dismutase (SOD1) gene have been identified in about 20% of the familial cases. The aim of this study was to investigate whether in a mouse model of ALS the cortical neurons developed hyperexcitability due to intrinsic properties of the single cell. We first examined the passive membrane properties and the pattern of repetitive firing in cultured cortical neurons from Control mice and transgenic mice expressing high levels of the human mutated protein (Gly(93)-->Ala, G93A). The former did not display significantly differing values between Control and G93A cortical neurons. However, the threshold potential and time of the first action potential decreased significantly and the firing frequency increased significantly in the G93A compared to Control neurons. The analysis of the voltage-dependent sodium currents revealed that the fast transient sodium current was unaffected by the SOD1 mutation whereas the persistent sodium current was significantly higher in the mutated neurons. Finally, Riluzole, a selective blocker of the persistent sodium current at low concentrations, decreased the firing frequency in G93A neurons, strongly indicating an involvement of this current in the observed hyperexcitability. These are the first data that demonstrate an intrinsic hyperexcitability in the G93A cortical neurons due to a higher current density of the persistent sodium current in the mutated neurons and open up new prospects of understanding ALS disease etiopathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Biophysical Phenomena
  • Cells, Cultured
  • Cerebral Cortex / pathology*
  • Disease Models, Animal
  • Electric Stimulation
  • Excitatory Amino Acid Antagonists / pharmacology
  • Humans
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Membrane Potentials / physiology
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques / methods
  • Riluzole / pharmacology
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / physiology*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Tetrodotoxin / pharmacology


  • Excitatory Amino Acid Antagonists
  • Sodium Channel Blockers
  • Sodium Channels
  • Tetrodotoxin
  • Riluzole
  • SOD1 G93A protein
  • Superoxide Dismutase