Nav12 in Demyelinated Axons in EAE

Figs. 1 and 2 demonstrate an increase in Nav1.2 expression along axons in this animal model of inflammatory demyelination. As shown in Fig. 1, there is a reduction in frequency of Nav1.6-positive nodes (84.5% Nav1.6-immunopositive nodes in controls vs. 32.9% in EAE), and increased frequency of Nav1.2-positive nodes (11.8% Nav1.2 immunopositive nodes in controls vs. 74.9% in EAE). It is not yet clear whether the Nav1.2-expressing nodes are formed by remyelination or by replacement of Nav1.6 with Nav1.2 at preexisting nodes.

There are also a large number of demyelinated axons in EAE, which appear as linear axonal profiles lacking an association with myelin basic protein. Use of the optic nerve as an experimental model permits the unequivocal

Figure I Histogram demonstrating a significant reduction in percentage of Nav1.6-positive nodes with robust Caspr (left panel) and increased percentage of Na 1.2-positive nodes with robust Caspr (right panel) in EAE. *P < 0.005. V

identification of demyelinated (as opposed to nonmyelinated) axons, as virtually 100% of the axons in this tract are normally myelinated. Diffuse sodium channel immunostaining for Nav1.2 or Nav1.6 extends for tens of microns along the fiber axis in these demyelinated axons, as illustrated in Fig. 2 (Craner, 2003a). The increase in Nav1.2 immunostaining is accompanied by upregulated levels of Nav1.2 mRNA within

Figure 2 Changes in Nav1.6 and Nav1.2 expression in optic nerve axons in EAE. Representative digital images of sections of optic nerve from control (A and B) and EAE (C—F). A and B demonstrate nodes with robust Caspr with Nav1.6 (A) and, less commonly, (B) Nav1.2-positive immunostaining (yellow arrowhead) in control optic nerve. C—E and D-F demonstrate a pattern of progressive nodal disruption. Some nodes show weak and diffuse Caspr immunostaining (inset, C). There is a loss of Nav1.6 immunostaining (C and E) and an increase in Nav1.2 immunostaining (D and F) at nodes. Some demyelinated axonal profiles display diffuse Nav1.6 (E) and Nav1.2 (D, F) immunostaining (unfilled white arrows, D, E, F), which can extend for tens of microns along the fiber axis.

Figure 2 Changes in Nav1.6 and Nav1.2 expression in optic nerve axons in EAE. Representative digital images of sections of optic nerve from control (A and B) and EAE (C—F). A and B demonstrate nodes with robust Caspr with Nav1.6 (A) and, less commonly, (B) Nav1.2-positive immunostaining (yellow arrowhead) in control optic nerve. C—E and D-F demonstrate a pattern of progressive nodal disruption. Some nodes show weak and diffuse Caspr immunostaining (inset, C). There is a loss of Nav1.6 immunostaining (C and E) and an increase in Nav1.2 immunostaining (D and F) at nodes. Some demyelinated axonal profiles display diffuse Nav1.6 (E) and Nav1.2 (D, F) immunostaining (unfilled white arrows, D, E, F), which can extend for tens of microns along the fiber axis.

the retinal ganglion cells, which give rise to demyelinated optic nerve axons (Fig. 3). Thus the emergence of increased numbers of nodes expressing Nav1.2, and of extensive regions of Nav1.2 along demyelinated axons, appears to reflect upregulated synthesis of Nav1.2 channels.

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