Journal
BRAIN
Volume 126, Issue -, Pages 1552-1561Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awg153
Keywords
sodium channels; demyelination; multiple sclerosis; visual pathways; nodes of Ranvier
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Myelinated fibres are characterized by the aggregation of Na(v)1.6 sodium channels within the axon membrane at nodes of Ranvier, where their presence supports saltatory conduction. In this study, we used immunocytochemical methods to study the organization of sodium channels along axons in experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis. We studied axons within the optic nerve, a CNS tract commonly affected in multiple sclerosis, and their cell bodies of origin (retinal ganglion cells), using subtype-specific antibodies generated against sodium channel subtypes Na(v)1.1, Na(v)1.2, Na(v)1.3 and Na(v)1.6, which previously have been shown to be expressed by retinal ganglion cells. We demonstrate a significant switch from Na(v)1.6 to Na(v)1.2 expression in the optic nerve in EAE; there was a reduction in frequency of Na(v)1.6-positive nodes (84.5% Na(v)1.6-immunopositive nodes in control versus 32.9% in EAE) and increased frequency of Na(v)1.2-positive nodes (11.8% Na(v)1.2 immunopositive nodes in control versus 74.9% in EAE). Moreover, we observed a significant increase in the number of linear (presumably demyelinated) axonal profiles demonstrating extended diffuse immunostaining for Na(v)1.2 in EAE versus control optic nerves. These changes within the optic nerve are paralleled by decreased levels of Na(v)1.6 and increased Na(v)1.2 protein, together with increased levels of Na(v)1.2 mRNA, within retinal ganglion cells in EAE. Our findings of a loss of Na(v)1.6 and increased expression of Na(v)1.2 suggest that electrogenesis in EAE may revert to a stage similar to that observed in immature retinal ganglion cells in which Na(v)1.2 channels support conduction of action potentials along axons.
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