The long-term objective of this proposal is to elucidate the physiology of nerve functions in mammalian myelinated fibers under both normal physiological conditions and conditions in which the normal Schwann cell-axon relation has been disturbed. Different types of electrophysiological techniques will be used to measure various specific membrane properties on single mammalian myelinated axons and Schwann cells in which the relations between them have been experimentally disturbed. Voltage clamp experiments will be performed on single mammalian myelinated fibers. The complementary distribution of ionic channels along a mammalian myelinated axon, with Na channels clustered at the node and K channels located in the paranode, will be examined. The effect of perturbing the Schwann cell-axon relation on this channel distribution will be explored. Furthermore, the role of the internodal K channels that normally hide under the myelin will be examined. In particular, the hypothesis that these internodal K channels play a crucial role in supporting the resting potential of a node will be tested. The mechanisms that normally cluster Na channels at a node of Ranvier will be examined and the requirement of a normal Schwann cell-axon relation for such a clustering will be explored. Relatedly, the lateral diffusion of Na channels from a node to an internode will be measured and the coefficient of lateral diffusion of Na channels in a mammalian fiber will be calculated. A unique feature of this proposal is the application of the new and powerful patch clamp to single myelinated fibers. A high resolution mapping of the spatial distribution of ionic channels in demyelination can be achieved. Specifically, the kinetic properties and the spatial densities of the new internodal Na channels that appear after chronic demyelination will be examined. Such measurements on channel redistribution will then be correlated with functional recovery. Finally, the expression of excitable membrane properties on mammalian Schwann cells will be explored with the patch clamp technique. Specifically, the influence of development and axon contact on the expression of Na and K channels on mammalian Schwann cells will be examined.
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