Within the normal adult nervous system, Nav1.6 is the predominant sodium channel that is clustered at mature nodes of Ranvier (Caldwell et al., 2000). The aggregation of sodium channels within the nodal axon membrane, however, is the endpoint of a complex developmental sequence. At early stages before glial ensheathment, premyelinated axons display a low density of sodium channels that are distributed uniformly along the fiber (Black et al., 1982; Waxman et al., 1989). Aggregation of Nav1.6 channels within the nodal axon membrane occurs relatively late within the developmental sequence; Nav1.2 channels are first expressed (initially in a widely distributed, diffuse manner) in the membrane of premyelinated axons and then at immature nodes within CNS white matter, followed by a switch to Nav1.6 at mature nodes of Ranvier with completion of the myelin sheath (Boiko et al., 2001; Kaplan et al., 2001).
As subtype-specific sodium channel antibodies began to be developed, studies on myelin mutants yielded hints of a relationship between myelination and the specification of sodium channel subtype. In an early study on axons lacking myelin within the Shiverer mutant, Westenbroek et al. (1992) observed Nav1.2 along dysmyelinated tracts. In a more recent study on the same mutant model, Boiko et al. (2001) observed a lack of Nav1.6 and retention of Nav1.2 that was distributed along dysmyelinated axons. These studies, however, did not examine the distribution of Nav1.2 and Nav1.6 in demyelinated axons.
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