Focal and generalized seizure activity after local hippocampal or cortical ablation of NaV1.1 channels in mice

Abstract

Early onset seizures are a hallmark of Dravet syndrome. Previous studies in rodent models have shown that the epileptic phenotype is caused by loss‐of‐function of voltage‐gated Na_V1.1 sodium channels, which are chiefly expressed in γ‐aminobutyric acid (GABA)ergic neurons. Recently, a possibly critical role has been attributed to the hippocampus in the seizure phenotype, as local hippocampal ablation of Na_V1.1 channels decreased the threshold for hyperthermia‐induced seizures. However, the effect of ablation of Na_V1.1 channels restricted to cortical sites has not been tested. Here we studied local field potential (LFP) and behavior in mice following local hippocampal and cortical ablation of Scn1a, a gene encoding the α1 subunit of Na_V1.1 channels, and we compared seizure characteristics with those of heterozygous global knockout Scn1^‐/+ mice. We found a high incidence of spontaneous seizures following either local hippocampal or cortical ablation, notably during a transient time window, similar to Scn1a^‐/+ mice. Nonconvulsive seizure activity in the injected area was common and preceded generalized seizures. Moreover, mice were susceptible to hyperthermia‐induced seizures. In conclusion, local ablation of Na_V1.1 channels in the hippocampus and cortex results in focal seizure activity that can generalize. These data indicate that spontaneous epileptic activity may initiate in multiple brain regions in Dravet syndrome.