Abstracts

Rationale: SCN8A encephalopathy is a severe epilepsy syndrome caused by mutations in the SCN8A gene which encodes the voltage-gated sodium channel isoform NaV1.6. Previous studies using transgenic mouse models of SCN8A encephalopathy have demonstrated aberrant intrinsic excitability in pyramidal neurons in hippocampal and cortical regions. However, NaV1.6 is expressed in inhibitory interneurons, yet there have been no studies examining the effect of mutant SCN8A function on their intrinsic excitability. Appreciating how mutant NaV1.6 impacts the excitability of inhibitory interneurons is necessary to understand the network mechanisms that ultimately result in seizures, and will hopefully generate mechanistically-based novel therapeutic strategies.  Methods: We conducted whole-cell patch-clamp electrophysiology recordings in layer V cortical somatostatin-positive (SST) interneurons from adult (>8 weeks) WT and Scn8aD/+ mice, a validated transgenic mouse model of SCN8A encephalopathy. In the current-clamp configuration, we recorded intrinsic excitability, while in the voltage-clamp configuration, we measured the magnitude and voltage-dependence of voltage-gated sodium channel currents. Results: At steady-state conditions, we observed that SST interneurons from Scn8aD/+ mice were more excitable than WT controls, having elevated spontaneous firing frequencies (***P<0.001, n=33 neurons per group). However, we found that Scn8aD/+ SST interneurons were prone to action potential (AP) failure at high-intensity and frequency current injections due in part to depolarization block. In our characterization of the voltage-gated sodium channel currents in Scn8aD/+ SST interneurons (n=13 neurons), we found that persistent sodium currents were elevated (*P<0.05) compared to WT controls (n=9 neurons). Conclusions: Our results reveal a novel mechanism for network hyperexcitability in SCN8A encephalopathy: Elevated persistent sodium currents drive initial hyperexcitability of SST interneurons but increases AP failure at high stimulation intensity and frequency due to depolarization block. We propose that frequency-dependent SST interneuron AP failure would permit runaway excitation in pyramidal neurons resulting in network hyperexcitability underlying and seizures.  Funding: Research was supported by NIH R01 NS103090 awarded to MKP and Robert R. Wagner fellowship to ERW.