The goal of this project is to examine the relation between partial remyelination in the injured nervous system and the clinically significant problem of action potential conduction block. These studies will be performed in a guinea pig model of chronic spinal cord injury and will involve intracellular recording from myelinated nerve fibers within strips of spinal cord white matter isolated in artificial media. The physiological responses and conduction properties of these fibers will be recorded and related to the characteristics of their myelin sheaths, as determined by intracellular injection of the marker biocytin and subsequent morphologic reconstruction from serial sections. This information will be used to explore the relation between morphological and physiological changes using computer based mathematical models of action potential conduction. A broader survey of the range of myelination deficits in these white matter tracts will also be performed by conventional means of osmium tetroxide fixation and teasing apart of single fibers. A particular goal of this study will be to identify differences between axons that respond and those that do not respond to the application of 4- aminopyridine (4-AP) with a change in the temperature of conduction block or of frequency-response characteristics. Previous experiments have shown that 4-AP, a potassium channel blocking drug, can restore conduction of impulses in some axons of chronically injured spinal cord that otherwise fail to conduct at physiological temperature. The same drug has also been shown to improve neurologic function in animals and human subjects with chronic spinal cord injury, and may prove to be a useful symptomatic treatment, particularly in some cases of incomplete spinal cord injury. It is important to understand the cell physiological basis of these responses, in order to optimize this approach to reducing functional deficits following injury to the nervous system. The experiments will address the potential role of a number of factors in the relation between changes in the myelination of central axons and their conduction characteristics. These include the dimensions of node and internode, with attendant effects on impedance matching; changes in the resting potential of the nerve fiber and their influence on excitability; alterations in the accumulation of extracellular potassium as a result of action potential transmission; and direct involvement of internodal ion channels exposed to large electrical potential transients as a result of dramatic reductions of myelin sheath thickness. A mathematical model of the myelinated axon will be used to explore the possible interaction between these factors and the blockade of voltage-dependent potassium channels, equivalent to the effects of CAP and other drugs.
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