Cerebellum-Related Characteristics of Scn8a-Mutant Mice

Among ten sodium channel alpha-subunit genes mapped in human and mouse genomes, the SCN8A gene is primarily expressed in neurons and glia. Mice with two types of Scn8a null mutations-Scn8a (med) and Scn8a (medTg) -live for only 21-24 days, but those with incomplete mutations-Scn8a (medJ) and Scn8a (medJo) -and those with knockout of Scn8a only in cerebellar Purkinje cells live to adult age. We review here previous work on cerebellum and related regions of Scn8a mutant mice and include some newer immunohistochemical and microchemical results. The resurgent sodium current that underlies the repeated firing of Purkinje cells is reduced in Scn8a mutant and knockout mice. Purkinje cells of mutant mice have greatly reduced spontaneous activity, as do the analogous cartwheel cells of the dorsal cochlear nucleus. Up-regulation of GABA(A) receptors in regions to which Purkinje cells project may partially compensate for their decreased activity in the mutant mice. The somata of cerebellar Purkinje cells of Scn8a (medJ) and Scn8a (medJo) mice, as revealed by PEP-19 immunoreaction, are slightly smaller than normal, and their axons, especially in Scn8a (medJo) mice, sometimes show enlargements similar to those in other types of mutant mice. Density of GABA-like immunoreactivity is decreased in Purkinje somata and regions of termination in deep cerebellar and vestibular nuclei of Scn8a (medJ) mice, but measured GABA concentration is not significantly reduced in microdissected samples of these regions. The concentrations of taurine and glutamine are significantly increased in cerebellar-related regions of Scn8a (medJ) mice, possibly suggesting up-regulation of glial amino acid metabolism.