Abstracts

Rationale: De novo gain-of-function mutations in SCN8A, which encodes voltage-gated sodium channel isoform Na_V1.6, are causative of SCN8A encephalopathy, a severe genetic epilepsy syndrome. Patients have early-onset seizures, severe cognitive impairment, motor dysfunction, and significant risk of Sudden Unexplained Death in Epilepsy (SUDEP). Many patients are refractory to current treatments. Methods: We conducted whole-cell patch-clamp electrophysiological recordings of subiculum neurons from wild-type (WT) control and Scn8a^D/+ mice, a transgenic model of SCN8A encephalopathy. We investigated the effects of the novel sodium channel blocker Prax330 at 1 µM on both persistent and resurgent sodium currents as well as intrinsic and synaptic excitability. Results: Our results show that persistent and resurgent sodium currents are elevated in subiculum neurons from Scn8a^D/+ mice compared to WT mice leading to aberrant action potential (AP) burst morphology in a subset of neurons. Prax330 (1 µM) decreased both persistent and resurgent sodium currents and normalized abnormal burst-firing in Scn8a^D/+ mice without affecting the AP morphology of WT neurons. Interestingly, we found that Prax330 (1 µM) was able to reduce the number synaptically-evoked APs from Scn8a^D/+ neurons without diminishing the synaptic excitability of WT neurons. Conclusions: Our data suggest that elevated persistent and resurgent sodium currents drive abnormal subiculum excitability in SCN8A encephalopathy. Additionally, these findings support Prax330 as a novel anticonvulsant. Funding: Research was supported by NIH R01 NS103090. Prax330 was provided by Praxis Precision Medicines.