The proposed experiments will investigate the electrophysiological properties of myelinated axons and motor nerve terminals in frog, lizard and rat. We have developed intra-axonal recording techniques that permit the study of slow potential changes important in modulating axonal excitability. Our studies have already identified an unexpectedly slow component in the passive voltage response of these axons, and have demonstrated that action potentials are followed by a prolonged depolarizing afterpotential correlated with an increase in axonal excitability. Both these slow potentials can be accounted for by a revised electrical model that allows the large capacitance of the internodal axolemma to charge slowly during applied currents, and discharge slowly thereafter. We have used this revised electrical model to evaluate the effective resistances of the nodal and internodal axolemma and the myelin sheath, by analyzing the passive voltage response recorded in the axon. We also describe a modified voltage-clamp technique for measuring these resistances. These analytical techniques will be used to determine the mechanisms underlying changes in axonal passive properties and the depolarizing afterpotential produced by depolarization, potassium channel blocking agents, anti-myelin antibodies, and temperature changes, and to explore preliminary indications that repetitive axonal discharge leads to a transient reduction in the effective resistance of the myelin sheath. Other experiments will attempt to localize the major leakage pathways through or under the myelin sheath and to measure the frequency dependence on the axonal space constant. We will also attempt to localize and characterize slow ionic currents revealed by intra-axonal recordings. The proposed studies of myelin leakage pathways and slow ionic currents will expand our understanding of changes in axonal excitability following repetitive stimulation. The studies of physiological modulation of the myelin leakage resistance may suggest novel strategies for overcoming conduction block in demyelinating disorders.
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