Abstracts

Rationale: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Approximately 30% of epileptic patients have treatment resistant (refractory) seizures. Mesial temporal lobe epilepsy (MTLE), the most common form of refractory epilepsy, is characterized by spontaneous seizures, hippocampal sclerosis, and neuropsychological deficits. Dravet syndrome (DS), caused by loss-of-function mutations in the SCN1A voltage-gated sodium channel, is also often refractory to available treatments. DS is a catastrophic epileptic encephalopathy associated with severe early life febrile seizures and epilepsy, intellectual disability and a 15-20% mortality rate. Our laboratory has demonstrated that mice with reduced activity of the Scn8a sodium channel have increased seizure resistance, and the co-expression of an Scn8a mutation in a mouse model of DS resulted in a dramatic amelioration of seizure phenotypes. Based on these observations, we hypothesize that selective targeting of Scn8a might provide a clinically efficacious strategy for the treatment of refractory epilepsies. Methods: To test this hypothesis, we selectively knocked down Scn8a expression in the hippocampus of mouse models of MTLE and DS (Scn1a^+/-). Reduced Scn8a expression was achieved by injection of an adeno-associated viral vector expressing a short hairpin RNA against Scn8a (AAV-3). Control mice received a scrambled AAV construct (AAV-GFP). Continuous video/EEG analysis was performed to monitor spontaneous seizure activity. Results: Results from the mouse model of MTLE suggest reduced seizure frequency during the recording period in the AAV-3 treated mice compared to controls (t = 3.955, p < .001). In the mouse model of DS, we observed significantly increased resistance to induced seizures in both AAV-3-injected Scn1a^+/- (p < .05) and AAV-3-injected WT littermates (p < .001) when compared to controls (N = 7-11 per group). The average lengths of the detected spontaneous seizures were significantly shorter in AAV-3 injected Scn1a^+/- mutants compared to AAV-GFP injected mutants (p < .05; N = 8/treatment). Conclusions: In summary, the selective reduction of Scn8a expression in the hippocampus might provide a novel strategy for the treatment of some forms of refractory epilepsy. Source of Funding: Human Disease Genetics T32 Training Grant (5T32MH087977-05 to JCW); NIH grant (R01 NS072221 to AE)