CONTRIBUTION OF THE VOLTAGE-GATED SODIUM CHANNEL NAV1.6 AND TOLL LIKE RECEPTOR 2 IN THE PATHOPHYSIOLOGY OF EAE
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Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and neurodegenerative disorder of the central nervous system (CNS) with the highest worldwide prevalence existing in Canada and affecting over 3000 Nova Scotians. MS is characterized by the autoimmune-mediated destruction of myelin and axons in the CNS and has been linked to inflammatory processes that activate the immune system. The most recent understanding of the mechanisms associated with the development of MS suggests that the inflammatory processes in the early stages of the disease trigger a cascade of events including microglial activation, the release of reactive mediators, and mitochondria damage, which subsequently leads to axonal damage. Axonal degeneration, one of the hallmarks of the disease and a non-reversible process, leads to several neurological disabilities including visual impairment and vision loss. However, the mechanisms underlying axonal degeneration remain unclear. This thesis sought to characterize the impact of two key regulatory molecules: the voltage-gated sodium channel Nav1.6 and the Toll-like receptor 2, a component of the innate immune system, in the pathogenesis of EAE. To this end, I used experimental autoimmune encephalomyelitis (EAE), a rodent model that recapitulates key aspects of the human disease. I investigated the role of voltage-gated sodium channels (especially Nav1.6), which have previously been linked to axonal degeneration and loss (Chapter 2) by gene targeting in the retina and optic nerve. We extended these studies to determine the impact of the reduction of Nav1.6 in mice heterozygous for a null-allele of Scn8a. (Chapter 3). This in vivo study is the first to link a reduction of Nav1.6 in EAE to immune profile changes, such as a reduction of inflammation marked by decreased IL-6 in the plasma and myeloid cell infiltration in the optic nerve. Analysis of murine bone-marrow-derived mast cell (BMMCs) cultured in vitro, suggest a potential role of Nav1.6 in regulating the inflammatory process during EAE and LPS challenge. Additionally, I investigated the impact of TLR2 in brain inflammation and optic nerve axonal damage (Chapter 4). I found that the absence of TLR2 was associated with reduced inflammation in the periphery and within the CNS, including in blood, spleen, and brain, which is marked by decreased myeloid cells, such as Gr-1+/CD11b+ cells, chemokines in the plasma, and pro-inflammatory cytokines in the brain. The present study provides novel information by highlighting the role of TLR2 and Nav1.6 in EAE. This knowledge expands our understanding and ultimately promotes further investigation to target these molecules and unmask the mystery of their roles in MS.