Altered ionic conductances in axons of transgenic mouse expressing the human neurofilament heavy gene: A mouse model of amyotrophic lateral sclerosis

Exp Neurol. 2000 Jun;163(2):414-21. doi: 10.1006/exnr.2000.7378.


Neurofilaments (NFs; made by copolymerization of three intermediate filament proteins NF-L, NF-M, and NF-H, for light, medium, and heavy) constitute the most abundant cytoskeletal structure in large myelinated axons. The presence of aberrant NF accumulation has been associated with neurodegenerative diseases (such as ALS). The possible causal role of NF in neurodegeneration has been supported by studies on recently available transgenic mice in which expression of human NF-H (hNF-H +/+) leads to overt neuropathy. We have examined electrophysiological properties of myelinated axons in hNF-H +/+ mice using intraaxonal microelectrode recording from isolated sciatic and tibial nerves. Transgenic mice showed several deficits in physiological properties of low threshold myelinated fibers: conduction velocity and resting membrane potential were significantly decreased (20 +/- 1.6 vs 40 +/- 2 m/s; -71.3 +/- 0.9 vs -75.5 +/- 0.5 m/s; mean +/- SE; n = 25; 22 degrees C). While the amplitude of action potentials was of comparable size (82 +/- 5 vs 86 +/- 3 mV) duration of action potential (at half-amplitude, AP/2) in hNF-H +/+ was significantly prolonged (0.82 +/- 0.02 vs 0.65 +/- 0.02 ms). Voltage-current properties of axonal membrane indicate a significant decrease in inward and outward rectification. Occasionally, impaled axons of hNF-H +/+ showed membrane oscillations and repetitive activity (reminiscent of fasciculations) never observed in normal animals. These results are compatible with an imbalance between ion conductances in axons from transgenic animals (an increase in Na(+) and a decrease in K(+) conductances), in agreement with recent suggestion based on clinical studies on ALS patients (H. Bostock et al., 1995, Brain 118, 217-225). One may hypothesize that these changes could contribute to neurodegenerative processes (i.e., via an increase in [Na(+)](i)), as well as clinical symptoms (fasciculations) observed in patients with degenerative motor neuron diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology*
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Axons / physiology*
  • Disease Models, Animal*
  • Humans
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neural Conduction / physiology
  • Neurofilament Proteins / genetics
  • Neurofilament Proteins / metabolism*


  • Neurofilament Proteins
  • neurofilament protein H