Focal and generalized seizure activity after local hippocampal or cortical ablation of Na_V1.1 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 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.

A hyperthermic seizure unleashes a surge of spreading depolarizations inScn1adeficient mice

“…This evidence suggests that disease progression by a febrile seizure can occur independent of developmental stages, and that the exacerbation of phenotype is not solely a developmental defect, but likely involves a proexcitatory plasticity mechanism. This is consistent with studies demonstrating that postnatal Scn1a deletion can create an epileptic encephalopathy similar to the genomic model 32,33 , and also that the disease phenotype can be reversed or ameliorated when Scn1a expression is recovered at a juvenile age 34–36 . These findings suggest a life-long risk of exacerbation of disease to severe epilepsy encephalopathy, but also a potential for reversal of disease if the underlying mechanism can be appropriately targeted.…”

Transfer of SCN1A to the brain of adolescent mouse model of Dravet syndrome improves epileptic, motor, and behavioral manifestations

“…Using this tool, we have found that the need for homogeneous and widespread transgene expression is not as stringent as predicted in DS. The hippocampus is considered an important target for this disease, 34,35 but we found that HAdV5 vectors administered in this location reached a relatively low number of neurons and did not transduce neighboring structures. Injection in the cortex obtained efficient but locally restricted transgene expression, while cerebellum and especially basal ganglia were more permissive for vector transduction, in agreement with previous reports.…”

Clocking Epilepsies: A Chronomodulated Strategy-Based Therapy for Rhythmic Seizures

“…Remarkably, a mutation in SCN1A , voltage-gated sodium channel alpha subunit 1 (VGSC), causes over 80% of Dravet syndrome cases [ 40 , 243 ]. Several knockout rodent models have been generated for Dravet syndrome [ 244 , 245 ], whereas zebrafish homozygous scn1lab −/− mutants have also been used as an epilepsy model [ 246 ]. Except for α subunit, β subunit ( Scn1b ), type 2 ( Scn2a ), and type 8 ( Scn8a ) have also been used as genetic models for epilepsy in mice.…”