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Departments of
1 Physiology
2 Institute for Neuroscience
3 Neurology
4 Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Mutations in the enzyme superoxide dismutase 1 (SOD1) initiate a progressive motoneurone degeneration in amyotrophic lateral sclerosis (ALS). Transgenic mice overexpressing this mutation develop a similar progressive motoneurone degeneration. In spinal motoneurones cultured from presymptomatic mice expressing the glycine to alanine mutation at base pair 93 (G93A) SOD1 mutation, a marked increase in the persistent component of the Na+ current was observed, without changes in passive properties. This increase only enhanced neuronal excitability in high input conductance cells, as low input conductance cells exhibited a compensatory outward shift in the current remaining after Na+ blockade. High input conductance motoneurones tend to be large, so these results may explain the tendency of large motoneurones to degenerate first in ALS. Riluzole, at the therapeutic concentration used to treat ALS, decreased neuronal excitability and persistent Na+ current in G93A motoneurones to levels observed in the control motoneurones. Aberrations in the intrinsic electrical properties may be among the first symptoms to emerge in SOD1-linked ALS.
(Received 18 August 2004;
accepted after revision 11 January 2005;
first published online 13 January 2005)
Corresponding author C. J. Heckman: Department of Physiology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL 60611, USA. Email: c-heckman{at}north-western.edu
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