Depolarization block induction via slow NaV1.1 inactivation in Dravet syndrome

Dravet syndrome is a developmental and epileptic encephalopathy, characterized by the early onset of drug-resistant seizures and various comorbidities. Most cases of this severe and complex pathology are due to mutations of Na_V1.1, a sodium channel mainly expressed in fast-spiking inhibitory neurons. Layer et al. (Front. Cell. Neurosci. 15, 2021) showed that one of these mutations alters the voltage dependence of channel activation, as well as the voltage dependence and kinetics of slow inactivation. Implementing the three effects into a computational model, they predict that altered activation has the largest impact on channel function, as it causes the most severe firing rate reduction. Using a conductance-based model tailored to the dynamics of fast-spiking inhibitory neurons, we look deeper into slow inactivation. We exploit the timescale difference between this very slow process and the rest of the system to conduct a multiple-timescale analysis. We find that, upon prolonged stimulation, the onset of slow inactivation at lower voltage in mutant channels promotes depolarization block, another possible firing deficit aside from frequency reduction. The accelerated kinetics of slow inactivation in mutant channels hastens this transition. This suggests that slow inactivation alterations might for some Dravet variant contribute to the pathological mechanism.