Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy.

We previously found that genetic mutants with reduced expression or activity of Scn8a are resistant to induced seizures and that co-segregation of a mutant Scn8a allele can increase survival and seizure resistance of Scn1a mutant mice. In contrast, Scn8a expression is increased in the hippocampus following status epilepticus and amygdala kindling. These findings point to Scn8a as a promising therapeutic target for epilepsy and raise the possibility that aberrant overexpression of Scn8a in limbic structures may contribute to some epilepsies, including temporal lobe epilepsy.

SCN3A deficiency associated with increased seizure susceptibility.

Mutations in voltage-gated sodium channels expressed highly in the brain (SCN1A, SCN2A, SCN3A, and SCN8A) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Na1.3 α subunit, have been identified in patients with focal epilepsy.

Role of the hippocampus in Nav1.6 (Scn8a) mediated seizure resistance.

SCN1A mutations are the main cause of the epilepsy disorders Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Mutations that reduce the activity of the mouse Scn8a gene, in contrast, are found to confer seizure resistance and extend the lifespan of mouse models of DS and GEFS+. To investigate the mechanism by which reduced Scn8a expression confers seizure resistance, we induced interictal-like burst discharges in hippocampal slices of heterozygous Scn8a null mice (Scn8a(med/+)) with elevated extracellular potassium.

DNA methylation profiling in nanochannels.

We report the profiling of the 5-methyl cytosine distribution within single genomic-sized DNA molecules at a gene-relevant resolution. This method linearizes and stretches DNA molecules by confinement to channels with a dimension of about 250×200 nm(2). The methylation state is detected using fluorescently labeled methyl-CpG binding domain proteins (MBD), with high signal contrast and low background.