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Abstract
BackgroundIn multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) model of MS, the Nav1.6 voltage-gated sodium (Nav) channel isoform has been implicated as a primary contributor to axonal degeneration. Following demyelination Nav1.6, which is normally co-localized with the Na+/Ca2+ exchanger (NCX) at the nodes of Ranvier, associates with β-APP, a marker of neural injury. The persistent influx of sodium through Nav1.6 is believed to reverse the function of NCX, resulting in an increased influx of damaging Ca2+ ions. However, direct evidence for the role of Nav1.6 in axonal degeneration is lacking.MethodsIn mice floxed for Scn8a, the gene that encodes the α subunit of Nav1.6, subjected to EAE we examined the effect of eliminating Nav1.6 from retinal ganglion cells (RGC) in one eye using an AAV vector harboring Cre and GFP, while using the contralateral either injected with AAV vector harboring GFP alone or non-targeted eye as control.ResultsIn retinas, the expression of Rbpms, a marker for retinal ganglion cells, was found to be inversely correlated to the expression of Scn8a. Furthermore, the gene expression of the pro-inflammatory cytokines Il6 (IL-6) and Ifng (IFN-γ), and of the reactive gliosis marker Gfap (GFAP) were found to be reduced in targeted retinas. Optic nerves from targeted eyes were shown to have reduced macrophage infiltration and improved axonal health.ConclusionTaken together, our results are consistent with Nav1.6 promoting inflammation and contributing to axonal degeneration following demyelination.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of the central nervous system (CNS), affecting more than 2.5 million people worldwide [1, 2]
Retinas from eyes subjected to selective Nav1.6 targeting have increased retinal ganglion cell survival and reduced inflammation and reactive gliosis
Optic nerves from eyes subjected to selective Nav1.6 targeting have reduced demyelination and axonal loss
Summary
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of the central nervous system (CNS), affecting more than 2.5 million people worldwide [1, 2]. Voltage-gated sodium (Nav) channels have been implicated in the etiology of MS and EAE as a key factor in causing axonal degeneration. The Nav1.x channel family consists of nine different pore-forming alpha-subunits (Nav1.1–Nav1.9) which assemble with two of five nonpore-forming beta-subunits (β1, β1B, β2, β3, β4) These channels are present in motor and sensory axons in the peripheral nervous system (PNS) and cluster at nodes of Ranvier in CNS axons [9]. In multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) model of MS, the Nav1.6 voltage-gated sodium (Nav) channel isoform has been implicated as a primary contributor to axonal degeneration. Following demyelination Nav1.6, which is normally co-localized with the Na+/Ca2+ exchanger (NCX) at the nodes of Ranvier, associates with β-APP, a marker of neural injury. Direct evidence for the role of Nav1.6 in axonal degeneration is lacking
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