The correlation between pathology and neurological function in multiple sclerosis and other demyelinating diseases is poor, and the event responsible for the initial loss of neural function is unknown. This project seeks to investigate fundamental aspects of signal transmission in nerve fibers that have been altered by chemical or autoimmune mechanisms designed to reproduce the conduction failure seen in these diseases. This approach will allow an evaluation of the relation of immune reactions and structural changes to electrophysiological events. Using both optical techniques with voltage-identified single axons during all stages of demyelination and recovery. The immune properties of axons following their close association with T lymphocytes and macrophages. The possible involvement of cytokines and antibodies with ionic channels and with conduction will likewise be tested. During repetitive stimulation myelinated axons possess both refractory and hyper-excitable periods. In demyelinated fibers, with reduced safety factors, these phenomena are altered and lead to an axonal """"""""coding"""""""" of action potential patterns. The mechanisms responsible for this process will be investigated by following signals optically at several sites along an identified fiber. Ionic channels in the internodal axon membrane, which may be silent in normal function, incur considerable importance with demyelination, especially with respect to recovery of propagation. These channels will be characterized by single channel patch clamp analysis, and their control by pharmacological means explored. The restoration of function following demyelination depends upon glial association as well as on ionic channels, and it remains unclear how remission can occur in multiple sclerosis since remyelination in the central nervous system is rare and incomplete. Conduction in mammalian axons that have been demyelinated by autoimmune procedures will be followed optically in order to determine the minimum requirements for recovery. The experiments in this proposal will be performed both on peripheral fibers in the adult sciatic nerve, and in the central nervous system through the use of organotypic explant cultures and acute brain slices. Possible means of intervening in various steps of the disease process will be explored.
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