This proposal launches a major new initiative aimed at elucidating the function of voltage-sensitive ion channels in Schwann cells of mammalian myelinated nerves. The principle is to use promoters for myelin genes to alter selectively the expression of Schwann cell ion channels in intact nerves to test specific hypotheses about functions of Schwann cell channels. The emphasis is on potassium channels. Potassium channel genes in Schwann cells will be characterized and their expression pattern during myelination established. This expression pattern will then be altered in transgenic mice using myelin gene promoters. Transgenic sciatic nerves with an altered expression of potassium channel in Schwann cells will be examined for disrupted ionic buffering, abnormal myelination, and changes in axonal channel distribution. A minor emphasis is on sodium channels. A myelin-gene promoter is used to direct the expression of a foreign sodium channel to Schwann cells, which carries a distinct pharmacological 'tag', to test the hypothesis that Schwann cells transfer sodium channels to the axonal membrane at the node of Ranvier. This new approach for in vivo functional analysis of Schwann cell ion channels will be of general applicability to glial cells in other parts of the brain, and may potentially uncover novel linkages between ion channel dysregulation in glia and functional perturbation in demyelinating diseases.
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