: Myelinated axons are designed for rapid, reliable and efficient conduction of electrical signals. During the early organization of these fibers ion channels assume a highly heterogeneous distribution that contributes to successful function. Axonal voltage-dependent sodium channels, for example, are sequestered at high density at nodes of Ranvier, and are distributed at much lower levels under the myelin. Some specific subtypes of voltage-dependent potassium channels aggregate in paranodal regions, while others are more diffusely localized. This proposal seeks to define the cellular and molecular events involved in the interaction between neurons and glia that control ion channel sequestration. Both immunocytochemical and electrophysiological techniques are employed. Pathophysiology is a second major area of interest. The effector mechanism responsible for loss of conduction at early stages of demyelinating disease is not known and myelin damage may not be the sole determinant of function. This laboratory has preliminary evidence for two possible contributing factors, both of which involve disruption of Na+ channel function at nodes of Ranvier in autoimmune inflammatory disease of the nervous system. This proposal seeks to investigate the mechanisms responsible for these events in detail. It is also planned to examine recovery processes. For example, during remyelination new nodes of Ranvier appear at sites that formerly were internodal. In order for these nodes to be functional they require a high density of Na+ channels, and perhaps also paranodal K+ channels. This project is directed at the cellular and molecular mechanisms responsible for this reorganization. The ultimate goal is to develop strategies for therapeutic intervention in multiple sclerosis and other demyelinating diseases.
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