Brain, Vol. 118, No. 1, 217-225, 1995
© 1995 Oxford University Press
research-article |
Axonal ion channel dysfunction in amyotrophic lateral sclerosis
1The Sobell Department of Neurophysiology, Institute of Neurology London, UK 2The Department of Clinical Neurophysiology, The National Hospital for Neurology and Neurosurgery London, UK
Correspondence to:
Dr H. Bostock, Sobell Department of Neurophysiology, Institute of Neurology, Queen Square, London WC1N 3BG, UK
In amyotrophic lateral sclerosis (ALS) it is not known how or why the motor neurons die, but a clue is provided by observations that the dying cells discharge spontaneously, producing muscle fasciculations. The fasciculations can arise either proximally or distally in the motor unit, suggesting a widespread disturbance of membrane excitability. To test for this, we applied the technique of threshold electrotonus to ulnar motor axons at the wrist, comparing the responses to 100 ms polarizing currents in 11 ALS patients with those from 15 normal controls, six patients with benign fasciculations, 19 with lower motor neuron disorders and six with upper motor neuron disorders. We found that the motor axons of ALS patients, unlike those in the neurological control groups, responded abnormally to subthreshold depolarizing currents, becoming either more (seven cases) or much less excitable (four cases) than normal. Both types of abnormality could be reproduced in rat nerves in vitro, and in a computer model of human motor axons, by reducing voltage dependent potassium conductances. When sufficient potassium channels were blocked, the model axon became unstable and depolarized regeneratively, resulting in an abrupt fall in excitability. We conclude that the fasciculations in ALS are caused by an imbalance between functional sodium and potassium channels, and we propose that this ion channel dysfunction could also be responsible for the motor neuron degeneration in this disease.
ALS; fasciculation; nerve excitability; ion channels
Received October 20, 1994. Revised November 24, 1994. Accepted November 29, 1994.
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