Dataset Information

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

ABSTRACT: We previously found that genetic mutants with reduced expression or activity of Scn8a are resistant to induced seizures and that co-segregation of a mutant Scn8a allele can increase survival and seizure resistance of Scn1a mutant mice. In contrast, Scn8a expression is increased in the hippocampus following status epilepticus and amygdala kindling. These findings point to Scn8a as a promising therapeutic target for epilepsy and raise the possibility that aberrant overexpression of Scn8a in limbic structures may contribute to some epilepsies, including temporal lobe epilepsy. Using a small-hairpin-interfering RNA directed against the Scn8a gene, we selectively reduced Scn8a expression in the hippocampus of the intrahippocampal kainic acid (KA) mouse model of mesial temporal lobe epilepsy. We found that Scn8a knockdown prevented the development of spontaneous seizures in 9/10 mice, ameliorated KA-induced hyperactivity, and reduced reactive gliosis. These results support the potential of selectively targeting Scn8a for the treatment of refractory epilepsy.

SUBMITTER: Wong JC

PROVIDER: S-EPMC5760706 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Wong Jennifer C JC Makinson Christopher D CD Lamar Tyra T Cheng Qi Q Wingard Jeffrey C JC Terwilliger Ernest F EF Escayg Andrew A

Scientific reports 20180109 1

We previously found that genetic mutants with reduced expression or activity of Scn8a are resistant to induced seizures and that co-segregation of a mutant Scn8a allele can increase survival and seizure resistance of Scn1a mutant mice. In contrast, Scn8a expression is increased in the hippocampus following status epilepticus and amygdala kindling. These findings point to Scn8a as a promising therapeutic target for epilepsy and raise the possibility that aberrant overexpression of Scn8a in limbic ...[more]

PMID: 29317669

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Project description:Mesial temporal lobe epilepsy is the most common type of focal epilepsy and in its course often becomes refractory to anticonvulsant pharmacotherapy. A resection of the mesial temporal lobe structures is a promising option in these cases. However, approximately 30% of all patients remain with persistent seizures after surgery. In other words, reliable criteria for patients' outcome prediction are absent. To address this limitation, we investigated pre-surgical brain morphology of patients with unilateral left mesial temporal lobe epilepsy who underwent a selective amygdalohippocampectomy. Using support vector classification, we aimed to predict the post-surgical seizure outcome of each patient based on the pre-surgical T1-weighted structural brain images. Due to morphological gender differences and the evidence that men and women differ in onset, prevalence and symptomology in most neurological diseases, we investigated male and female patients separately. Thus, we benefitted from the capability to validate the reliability of our method in two independent samples. Notably, we were able to accurately predict the individual patients' outcome in the male (94% balanced accuracy) as well as in the female (96% balanced accuracy) group. In the male cohort relatively larger white matter volumes in the favorable as compared to the non-favorable outcome group were identified bilaterally in the cingulum bundle, fronto-occipital fasciculus and both caudate nuclei, whereas the left inferior longitudinal fasciculus showed relatively larger white matter volume in the non-favorable group. While relatively larger white matter volumes in the female cohort in the left inferior and right middle longitudinal fasciculus were associated with the favorable outcome, relatively larger white matter volumes in the non-favorable outcome group were identified bilaterally in the superior longitudinal fasciculi I and II. Here, we observed a clear lateralization and distinction of structures involved in the classification in men as compared to women with men exhibiting more alterations in the hemisphere contralateral to the seizure focus. In conclusion, individual post-surgical outcome predictions based on a single T1-weighted magnetic resonance image seem plausible and may thus support the routine pre-surgical workup of epilepsy patients.

Dataset Information

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

Publications

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

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