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

Abstract

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 (Scn8amed/+) with elevated extracellular potassium. Scn8amed/+ mutants exhibited reduced epileptiform burst discharge activity after P20, indicating an age-dependent increased threshold for induction of epileptiform discharges. Scn8a deficiency also reduced the occurrence of burst discharges in a GEFS+ mouse model (Scn1aR1648H/+). There was no detectable change in the expression levels of Scn1a (Nav1.1) or Scn2a (Nav1.2) in the hippocampus of adult Scn8amed/+ mutants. To determine whether the increased seizure resistance associated with reduced Scn8a expression was due to alterations that occurred during development, we examined the effect of deleting Scn8a in adult mice. Global Cre-mediated deletion of a heterozygous floxed Scn8a allele in adult mice was found to increase thresholds to chemically and electrically induced seizures. Finally, knockdown of Scn8a gene expression in the adult hippocampus via lentiviral Cre injection resulted in a reduction in the number of EEG-confirmed seizures following the administration of picrotoxin. Our results identify the hippocampus as an important structure in the mediation of Scn8a-dependent seizure protection and suggest that selective targeting of Scn8a activity might be efficacious in patients with epilepsy.

Altered gene expression profile in a mouse model of SCN8A encephalopathy

“…These data, together with the observed hippocampal astrocytosis, suggest that forebrain circuits are particularly affected. This conclusion is consistent with the observations of elevated persistent current and early afterdepolarization-like action potentials in hippocampal CA1 and CA3 neurons from these mice (Lopez-Santiago et al, 2015), and with the role of the hippocampus in seizure resistance due to Scn8a haploinsufficiency (Makinson et al, 2014). The lack of transcriptional changes in cerebellum is in agreement with the normal activity of cerebellar Purkinje cells from the D/+ mutant mice (MHM and JLW, unpublished observations).…”

Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy

“…The Scn8a med-jo allele also rescued the premature lethality of Scn1a +/− Dravet syndrome mice and extended the lifespan of Scn1a −/− mutants (45). Reduction of Scn8a expression by conditional deletion of a floxed allele in hippocampal neurons was protective against picrotoxin-induced seizures (46). Together with the present study, these studies demonstrate that increased Na v 1.6 activity can be associated with a predisposition to epilepsy, whereas reduced activity can be protective.…”

Remarkable alterations of Nav1.6 in reactive astrogliosis during epileptogenesis

“…Furthermore, only rats that previously experienced SE in our study exhibit the increase expression of Nav1.6, and this increase is profoundly seizure intensity-related. Moreover, it has been reported that reduced expression of Nav1.6 and inhibition of Nav1.6 activity can suppress the neuronal hyperexcitability121524. Thus, the increased Nav1.6 expression could be an important molecular alteration in the course of epileptogenesis.…”