Brain Advance Access published online on April 22, 2003
Brain, doi:10.1093/brain/awg153
© 2003 by Guarantors of Brain
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Article
1 Department of Neurology and PVA/EPVA Center for Neuroscience Research, Yale University School of Medicine, New Haven and Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT, USA
* Corresponding author. E-mail: stephen.waxman{at}yale.edu.
Received 7 January 2003
; revised 31 January 2003
; accepted 13 February 2003
Myelinated fibres are characterized by the aggregation of Nav1.6 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 Nav1.1, Nav1.2, Nav1.3 and Nav1.6, which previously have been shown to be expressed by retinal ganglion cells. We demonstrate a significant switch from Nav1.6 to Nav1.2 expression in the optic nerve in EAE; there was a reduction in frequency of Nav1.6-positive nodes (84.5% Nav1.6-immunopositive nodes in control versus 32.9% in EAE) and increased frequency of Nav1.2-positive nodes (11.8% Nav1.2 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 Nav1.2 in EAE versus control optic nerves. These changes within the optic nerve are paralleled by decreased levels of Nav1.6 and increased Nav1.2 protein, together with increased levels of Nav1.2 mRNA, within retinal ganglion cells in EAE. Our findings of a loss of Nav1.6 and increased expression of Nav1.2 suggest that electrogenesis in EAE may revert to a stage similar to that observed in immature retinal ganglion cells in which Nav1.2 channels support conduction of action potentials along axons.
Keywords: sodium channels; demyelination; multiple sclerosis; visual pathways; nodes of Ranvier
Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination
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