Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice.
ALS (amyotrophic lateral sclerosis) is an adult-onset and deadly neurodegenerative disease characterized by a progressive and selective loss of motoneurons. Transgenic mice overexpressing a mutated human gene (G93A) coding for the enzyme SOD1 (Cu/Zn superoxide dismutase) develop a motoneuron disease resembling ALS in humans. In this generally accepted ALS model, we tested the electrophysiological properties of individual embryonic and neonatal spinal motoneurons in culture by measuring a wide range of electrical properties influencing motoneuron excitability during current clamp. There were no differences in the motoneuron resting potential, input conductance, action potential shape, or afterhyperpolarization between G93A and control motoneurons. The relationship between the motoneuron's firing frequency and injected current (f-I relation) was altered. The slope of the f-I relation and the maximal firing rate of the G93A motoneurons were much greater than in the control motoneurons. Differences in spontaneous synaptic input were excluded as a cause of increased excitability. This finding identifies a markedly elevated intrinsic electrical excitability in cultured embryonic and neonatal mutant G93A spinal motoneurons. We conclude that the observed intrinsic motoneuron hyperexcitability is induced by the SOD1 toxic gain-of-function through an aberration in the process of action potential generation. This hyperexcitability may play a crucial role in the pathogenesis of ALS as the motoneurons were cultured from presymptomatic mice.
Kuo
Jason J
JJ
Department of Physiology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Schonewille
Martijn
M
Siddique
Teepu
T
Schults
Annet N A
AN
Fu
Ronggen
R
Bär
Peter R
PR
Anelli
Roberta
R
Heckman
C J
CJ
Kroese
Alfons B A
AB
D000200:Action Potentials / Q000502:physiology; D000409:Alanine / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D017097:Electric Impedance; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D005998:Glycine / Q000235:genetics; D066298:In Vitro Techniques; D016014:Linear Models; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000409:Alanine; D005998:Glycine