The overall objective of this proposal is to investigate mechanisms that underlie abnormal impulse generation and conduction block in demyelinated and remyelinated mammalian axons. An area of emphasis will be on the morphophysiological organization of potassium channels during the course of demyelination and remyelination. The role potassium conductances may have in regulating spike activity will studied for normal, demyelinated, and remyelinated axons. Intrinsic factors such as abnormal membrane properties and extrinsic factors such as axonal """"""""crosstalk"""""""" will be analyzed to determine what role they may have in the genesis of abnormal impulse generation in demyelinating lesions. Abnormal impulse generation may contribute to positive signs such as paresthesia or tingling in demyelinating diseases. One hypothesis to be tested in the proposed studies is that increases in spontaneous activity in demyelinating diseases such as multiple sclerosis contributes to activity-dependent excitability depression. The following specific points will be addressed: 1) What role do potassium channels have in regulating spike activity of normal central myelinated axons during the course of normal axon maturation? 2) What is the sequence of change in the effects of potassium channel blocking agents during demyelination and subsequent remyelination of central and peripheral nervous system axons? 3) What changes in action potential characteristics and membrane potential underlie abnormal impulse activity in demyelinated axons? 4) Can axonal """"""""cross-talk"""""""" be detected between demyelinated axons, and to what extent do electric field effects versus extracellular potassium ion accumulation contribute to """"""""cross-talk""""""""? 5) Can reducing abnormal impulse activity in demyelinated axons, with the anticonvulsants diphenylhydantoin and carbamazapine, reduce activity-dependent excitability depression and lead to the overcoming of conduction block? Completion of the proposed studies will increase our understanding of the sequence of change in the physiological properties of normal central and peripheral axons during maturation and on how these properties change in response to demyelination and remyelination. The effectiveness of anticonvulsants, on reducing spontaneous activity and allowing for some recovery from activity-dependent excitability depression will be assessed. It will be determined if such modulation of excitability can improve conduction through regions of demyelination.
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