Loss of Na super(+) channel beta 2 subunits is neuroprotective in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is a CNS disease that includes demyelination and axonal degeneration. Voltage-gated Na super(+) channels are abnormally expressed and distributed in MS and its animal model, Experimental Allergic Encephalomyelitis (EAE). Up-regulation of Na super(+) channels along demyelinated axons is proposed to lead to axonal loss in MS/EAE. We hypothesized that Na super(+) channel beta 2 subunits (encoded by Scn2b) are involved in MS/EAE pathogenesis, as beta 2 is responsible for regulating levels of channel cell surface expression in neurons. We induced non-relapsing EAE in Scn2b super(+) super( )/ super(+) and Scn2b super(-) super(/) super(-) mice on the C57BL/6 background. Scn2b super(-) super( )/ super(-) mice display a dramatic reduction in EAE symptom severity and lethality as compared to wildtype, with significant decreases in axonal degeneration and axonal loss. Scn2b super(-) super(/) super(-) mice show normal peripheral immune cell populations, T cell proliferation, cytokine release, and immune cell infiltration into the CNS in response to EAE, suggesting that Scn2b inactivation does not compromise immune function. Our data suggest that loss of beta 2 is neuroprotective in EAE by prevention of Na super(+) channel up-regulation in response to demyelination.