The proposed project is a continuation of studies of normal and abnormal myelinated nerve fibers in the peripheral and central nervous systems. The primary emphasis will be on two specialized regions, the node of Ranvier and the paranodal region, at both of which the axon forms specialized junctions with glial cells. The axoglial interrelationships at these sites will be examined by means of freeze-etching methods to clarify details of the membrane surfaces and of the structural connections between them and with cytoplasmic elements. The purpose of this analysis is to clarify: 1. the role the respective axoglial junctions in axolemmal differentiation, particularly with respect to the mechanism by which sodium channels accumulate and are retained in the nodal axolemma, and 2. the structural basis for attachment of the myelin sheath to the axon in the paranodal region. In addition, models of both peripheral and central axonopathy will be studied in order to determine the nature and sequence of changes in nodal and paranodal regions of the axolemma and in the axoglial interactions resulting from primary axon damage in comparison with the changes resulting from primary pathology of the myelin-forming cells. The emphasis here will be on changes that may affect the distribution of sodium channels, which may in turn underlie the pathophysiology of the respective types of neuropathy. Finally the development of axoglial junctions will be studied in a myelin-deficient mutant in order to assess the role of aberrant junctions in the development of the structural and functional abnormalities in these animals. The long term goal of all of these studies is to clarify the structural basis for pathophysiology in a variety of congenital and acquired diseases affecting myelinated nerve fibers.
