Slow sodium-dependent potential oscillations contribute to ectopic firing in mammalian demyelinated axons.
Ectopic action potentials can arise at regions of axonal demyelination, and are believed to contribute to a range of symptoms in patients with demyelinating conditions such as multiple sclerosis. The mechanism(s) by which the ectopic impulses are generated are uncertain. We have previously shown that such ectopic activity can result from inward potassium currents. Paradoxically, the potassium channel blocking agent 4-aminopyridine (4AP) can sometimes cause ectopic activity in demyelinating lesions. To study this phenomenon we have made intra-axonal recordings of ectopic activity in demyelinated axons, both in the presence and absence of 5 mM 4AP. 4AP promoted a pattern of firing which was observed, albeit less frequently, in demyelinated axons in the absence of this drug, namely trains of single impulses, or trains of short, high-frequency bursts of impulses. When recorded close to the demyelinated lesion, the impulses were generated by an underlying, almost sinusoidal oscillation of the membrane potential. This oscillation was abolished by the sodium channel blocking agent tetrodotoxin (0.1-1 microM). We conclude that the ectopic spiking induced by 4AP is generated by membrane potential oscillations associated with the site of demyelination. The sodium-dependent current underlying these oscillations, together with the prolonged inward potassium currents which we have previously described, may contribute to the generation of ectopic discharges in a range of disorders of myelinated axons.
Kapoor
R
R
Department of Neurology, UMDS, London, UK.
Li
Y G
YG
Smith
K J
KJ
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D003711:Demyelinating Diseases / Q000503:physiopathology*; D004594:Electrophysiology; D008297:Male; D026902:Potassium Channel Blockers; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011930:Reaction Time; D012584:Sciatic Nerve / Q000187:drug effects / Q000503:physiopathology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013779:Tetrodotoxin / Q000494:pharmacology
D026902:Potassium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D015761:4-Aminopyridine