Pathophysiology of movement disorders resulting from conditional inactivation of the voltage -gated sodium channel <italic>Scn8a</italic>.

Abstract

<italic>Scn8a</italic> encoding the voltage-gated sodium channel alpha subunit Na_V1.6 is widely expressed in neurons and glia of the central and peripheral nervous system. Na_V1.6 is the major sodium channel at mature nodes of Ranvier in myelinated axons and is also localized in neuronal soma, dendrites, axon initial segments and unmyelinated axons. Mice with mutations in <italic>Scn8a</italic> exhibit a spectrum of neurological disorders including ataxia, tremor, paralysis and dystonia. I examined the potential for genetic interactions between sodium channel genes by crossing mice carrying a hypomorphic allele of <italic>Scn8a</italic> with mice carrying null alleles in either of two other sodium channel subunits. No genetic interactions were observed between <italic>Scn8a</italic> and <italic>Scn2a</italic> or <italic>Scn2b </italic>, indicating that bigenic interactions between these genes are unlikely to cause neurological disease in human populations. I used gene targeting in mouse embryonic stem (ES) cells to generate a conditional, floxed allele of <italic>Scn8a</italic> for Cre mediated recombination. Homozygous <italic>Scn8a<super>flox/flox</super></italic> mice are viable and express normal levels of Na_V1.6 protein. Ubiquitous inactivation of <italic>Scn8a</italic> in crosses between <italic>Scn8a<super>flox/flox </super></italic> mice and ZP3-Cre mice recapitulated the lethal paralysis observed in <italic>Scn8a</italic> null mice. I then conditionally inactivated <italic> Scn8a</italic> in cerebellar Purkinje cells and granule cells to evaluate the contribution of Scn8a in these neurons to the development of movement disorders. Inactivation of <italic>Scn8a</italic> in Purkinje cells resulted in mild ataxia. Inactivation of <italic>Scn8a</italic> in both Purkinje cells and granule cells produced a severe ataxia, indicating that these two types of neurons are largely responsible for the ataxic phenotype of <italic>Scn8a </italic> mutant mice. With collaborators at other institutions, I demonstrated that Purkinje cells from mice with <italic>Scn8a</italic> inactivated in Purkinje cells are missing resurgent sodium currents normally produced by Na_V1.6. These mice lacking resurgent currents specifically in Purkinje cells exhibit motor deficits and impaired motor and associative learning. These experiments expand our understanding of the contribution of <italic> Scn8a</italic> to the development of movement disorders and neurological disease.