Freeze-fracture approaches to ionophore localization in normal and myelin-deficient nerves

(1) The principal result of freeze-fracture studies of myelinated axons is that the axolemma is clearly not uniform in its structure, but rather is highly differentiated in both paranodal and nodal regions. Thus, it is no longer correct to assume that the special physiological properties of myelinated nerve fibers derive only from the presence of the myelin sheath. The inhomogeneity of the axolemma must also be taken into account. (2) The nodal axolemma is characterized by a population of large intramembranous particles primarily in the E fracture face that may correspond to the voltage sensitive sodium channels known to be concentrated there. (3) Significant numbers of such particles also frequently occur in paranodal "lakes" and in the internodal axolemma immediately adjacent to the paranodal region. These are probably accessible, albeit slowly, by way of the narrow extracellular cleft between the paranodal junctional membranes. (4) In the absence of ensheathment by myelinating cells, axons fail to develop normal nodal and paranodal membrane specializations. (5) When ensheathed by abnormal myelinating cells, corresponding abnormalities develop in both nodal and paranodal specializations of the axolemma. (6) Demyelination results in dedifferentiation of axolemmal specializations. (7) It is concluded that development and maintenance of normal axolemmal differentiation requires interaction of the axon with myelinating cells. These cells thus serve not only to produce myelin but also to regulate axolemmal differentiation. Alterations in axolemmal structure following demyelination may significantly affect the physiological properties of the axons. Specifically, ionophore redistribution may underlie the development of either continuous or nonuniform conduction in some demyelinated fibers.