Scientific Reports

Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy

17 December, 2018

Jennifer C. Wong, Christopher D. Makinson, Tyra Lamar, Qi Cheng, Jefrey C. Wingard,Ernest F. Terwilliger & Andrew Escayg

Contributed by Sloka Iyengar

Scientific Reports 2018 Jan 9;8(1):126 doi: 10.1038/s41598-017-17786-0

Objective

Epilepsy is a common neurological disorder, but unfortunately, about one-third of people with epilepsy do not benefit from commonly-prescribed anti-epileptic drugs. Additionally, current medications may also have many side-effects. Hence, novel therapies for epilepsy are sorely needed. One of the targets that scientists have been working on is Scn8a. The Scn8a gene is responsible for production of Nav1.6, which is a sodium channel, and is responsible for maintaining proper levels of excitability throughout the brain.

Previous studies have found mutations in a different, but related sodium channel called Nav1.1 in certain epilepsy syndromes in humans, but the role of Nav1.6 in epilepsy has not been clearly defined. What has been observed, however, is an increase in Scn8a after seizures, and that a decrease in Scn8a can confer resistance against epilepsy.

In this study, the authors used a unique technique called small-hairpin-interfering RNA to reduce the expression of Scn8a. They then investigated the effects of the decrease in Scn8a in a mouse model of temporal lobe epilepsy.

Results

The authors first showed that their technique for targeting Scn8a (small-hairpin-interfering RNA) was able to successfully decrease levels of the Nav1.6 protein. The chemoconvulsant kainic acid was used to cause mesial temporal lobe seizures in experimental mice. Mice that had intact levels of Scn8a exhibited seizures following kainic acid administration as expected, but this was greatly reduced in mice that had lower levels of Scn8a. Hence, when compared to normal mice, fewer mice with decreased levels of Scn8a exhibited seizures.

Hippocampal gliosis is a feature of mesial temporal lobe epilepsy, and the authors of this study found that mice with decreased levels of Scn8a had lower levels of gliosis in the hippocampus as compared to mice with intact Scn8a.

Interpretation

These results in experimental mice show that a decrease in Scn8a may be protective against seizures in temporal lobe epilepsy. Although more experiments are critical to get a better picture, it could be that Scn8a can be a novel target for future therapies to effectively treat drug-resistant temporal lobe epilepsy. Methods to selectively and specifically decrease Scn8a in the hippocampus may prove to be valuable in decreasing seizures with the possibility of limited side-effects.

Summary for specialists