Here we show, for the first time, spontaneous cortical spreading depolarization (CSD) eventsthe electrophysiological correlate of the migraine aurain animals by using the first generated familial hemiplegic migraine type 3 (FHM3) transgenic mouse model. The mutant mice express L263V-mutated a1 subunits in voltage-gated Na V 1.1 sodium channels (Scn1a L263V ). CSDs consistently propagated from visual to motor cortex, recapitulating what has been shown in patients with migraine with aura. This model may be valuable for the preclinical study of migraine with aura and other diseases in which spreading depolarization is a prominent feature.

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Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na V 1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied h-c coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical h-c coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. h-c Coupling was partly restored by cannabidiol (CBD). Locally disrupting Na V 1.1 expression in the hippocampus or cortex yielded early attenuation of h-c coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells (BCs). Our results indicate attenuated h-c coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.

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 NaV1.1 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 NaV1.1 channels decreased the threshold for hyperthermia‐induced seizures. However, the effect of ablation of NaV1.1 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 NaV1.1 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 NaV1.1 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.