Ectopic activity in demyelinated spinal root axons of the rat.

1. We have provoked ectopic discharges from demyelinated rat spinal roots by applying 1 mM-4-aminopyridine (4-AP), and recorded membrane currents and action potentials extracellularly by spike-triggered averaging. The demyelination was caused by intrathecal injection of diphtheria toxin, 6-9 days previously. 2. Mapping the distribution of membrane currents in the vicinity of an ectopic site showed that in most cases (eight out of twelve recorded) the impulses arose from one end of a continuously conducting internode, and conducted in both directions. In the remaining cases the impulses also arose from a site of demyelination. 3. The 4-AP-induced activity resembled the activity occurring spontaneously in some preparations, and was often highly regular (5-20 Hz). Recordings of membrane potential revealed a pacemaker potential, which was localized to the site of impulse initiation. One ectopic site was tested with applied currents and found to have a linear current-frequency relation for steady currents. 4. The time course of the pacemaker potential resembled that of the small after-hyperpolarization seen in normal fibres, due to a slow K+ conductance (GKs). Tetraethylammonium and barium ions, which block GKs, made spontaneously active fibres fire much more rapidly, or to fire bursts of action potentials. 5. Possible mechanisms for these ectopic discharges are discussed. GKs appears to contribute to the pacing of the activity, but not its generation. The increased excitability of the active fibres could not be attributed directly to the loss of myelin, nor to extracellular K+ accumulation. We suggest that they may have been depolarized by stretch-activated or ligand-gated channels in the demyelinated axon membrane.