The role of sodium channel alpha and beta subunits in myelinating glia and demyelinating disorders.

Abstract

Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system (CNS) in which patients experience a variety of neurological symptoms resulting from demyelination, axonal degeneration and axonal loss leading to conduction block or aberrant conduction. Voltage-gated sodium channels (VGSCs) have been implicated in the pathogenesis of MS and its animal model, Experimental Allergic Encephalomyelitis (EAE). We previously generated a Scn2b (VGSC β2) null mouse which exhibits a 40-50% decrease in neuronal VGSC cell surface expression. We hypothesized that Scn2b deletion would result in neuroprotection in EAE due to a decrease in excitotoxicity. The goal of this thesis was to determine the role of VGSCs in CNS demyelinating disease and myelinating glia using three different systems: Scn2b null mice, human MS brain, and cultured rat oligodendrocytes. Scn2b deletion led to improved clinical outcome in the EAE model, with mice displaying less severe clinical symptoms, decreases in lethality, and reductions in axonal loss, degeneration and demyelination. In EAE, these mice also displayed alterations in subcellular localization and protein expression levels of the VGSC α subunit Nav1.1, a channel which has not been studied previously in demyelinating disease. We then translated these experiments to the study of post-mortem human brain. MS brain displayed increased Nav1.1 protein levels in white and grey matter and changes in expression of β subunits in glia as compared to control brain. Finally, we examined the expression of VGSC α and β subunits in cultured rat oligodendrocytes at two stages of differentiation. These cells displayed differential expression of α and β subunits, with VGSC α, β1 and β3 subunits expressed at both stages while β2 and β4 were expressed at low levels. To summarize, the results presented in this thesis implicate VGSC β2 and Nav1.1 subunits in the pathogenesis of CNS demyelinating disease in both human and mouse, and suggest roles for VGSC α and β subunits in myelinating glial cell precursors. VGSC β2 and Nav1.1 subunits may also offer novel targets for the development of therapeutics for the treatment of MS.Ph.D.Cellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/64629/1/homalley_1.pd