The proposed work is ultimately directed to elucidating the biophysical basis of nervous dysfunction in demyelinating disease. Changes will be sought in the pattern of distribution of sodium channels, or potassium channels, and of sodium pumps in the nerve membrane during the processes of normal myelination (in the newborn animal) and of demyelination, produced experimentally in a number of ways. A variety of electrophysiological and pharmacological techniques will be used. Voltage-clamp experiments will be done to determine the Hodgkin-Huxley parameters for mammalian myelinated nerve at different temperatures. Sodium and potassium currents in voltage-clamp experiments will be used to examine sodium and potassium channels. The sensitivity of the compound action potential to 4-aminopyridine will be used to study potassium channels in situations (e.g. demyelination) where voltage-clamping is not feasible. The electrophysiological consequence of myelination will be examined experimentally. Labelled saxitoxin will be used as a marker for sodium channels; a search will be made for a corresponding high affinity marker for potassium channels. Labelled ouabain will be used as a marker for sodium pumps. Particular attention will be paid to the electrophysiological properties of the myelinating cell in the PNS, the Schwann cell using the patch-clamp method. Astrocytes and oligodendrocytes will also be patch-clamped. STX binding will be examined also.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS012327-19
Application #
3394794
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1975-06-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
19
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Baker, M; Howe, J R; Ritchie, J M (1993) Two types of 4-aminopyridine-sensitive potassium current in rabbit Schwann cells. J Physiol 464:321-42
Utzschneider, D A; Thio, C; Sontheimer, H et al. (1993) Action potential conduction and sodium channel content in the optic nerve of the myelin-deficient rat. Proc Biol Sci 254:245-50
Howe, J R; Baker, M; Ritchie, J M (1992) On the block of outward potassium current in rabbit Schwann cells by internal sodium ions. Proc Biol Sci 249:309-16
Howe, J R; Ritchie, J M (1992) Multiple kinetic components of sodium channel inactivation in rabbit Schwann cells. J Physiol 455:529-66
Ritchie, J M (1991) Current perspectives in glial electrophysiology. Ann N Y Acad Sci 633:331-42

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