Mechanisms and Treatment of SCN8A Epileptic Encephalopathy

SCN8A epileptic encephalopathy is a devastating genetic epilepsy syndrome caused by mutations in the SCN8A gene which encodes the voltage-gated sodium channel isoform NaV1.6. Patients experience refractory seizures, cognitive impairments, motor dysfunction, and have a substantial risk for sudden unexpected death in epilepsy (SUDEP). Gaining a mechanistic understanding of SCN8A encephalopathy promises to provide insight not only into basic mechanisms of epilepsy and voltage-gated sodium channel function, but also into treatment strategies for patients. On principle, a mechanistic description of SCN8A encephalopathy will require a quantitative characterization of 1) How mutations in SCN8A alter ion channel function, 2) How neuronal intrinsic excitability is changed in various neuronal populations 3) How these neurons function dynamically in circuits to produce aberrant network hypersynchrony and 4) How behavioral seizures are generated. In this dissertation thesis, I have experimentally addressed a few of these outstanding questions and by clarifying the mechanisms of SCN8A encephalopathy, I have indicated potential novel avenues for therapies.
Using patient-derived SCN8A mutations expressed in cell-culture, I have experimentally investigated how SCN8A mutations alter NaV1.6 channel function. Additionally, I provide evidence that physiologically loss-of-function mutations in SCN8A, when inherited biallelically, are able to cause developmental and epileptic encephalopathy. Utilizing mouse models of SCN8A encephalopathy, I demonstrate aberrant neuronal excitability in various regions of the hippocampus which can be rescued by treatment of Prax330, a novel sodium channel inhibitor which is currently under investigation for treating SCN8A encephalopathy. To uncover a deeper understanding of seizures and SUDEP in SCN8A encephalopathy, we serendipitously found that mice with SCN8A mutations are sensitive to reflex seizures in response to high-intensity acoustic stimulation and that they have a developmentally-determined risk of seizure-induced sudden death. Using this novel model of seizures and SUDEP, our results indicate that sudden death occurs primarily due to seizure-induced respiratory arrest which can be rescued either by mechanical ventilation or activation of alpha-1 adrenergic receptor activity. Our results contribute a novel and superiorly efficient means for interrogating the mechanisms of seizure and SUDEP in mouse models of SCN8A encephalopathy and highlight important potential strategies for preventing SUDEP. Lastly, I characterized the contribution of specific neuronal populations to SCN8A encephalopathy and found important roles for both forebrain excitatory neurons as well as somatostatin-positive inhibitory interneurons underlying the mechanism of disease. As a whole, these results provide numerous important contributions to gaining a mechanistic understanding of SCN8A epileptic encephalopathy which is critical to developing better treatment approaches.