Abstracts

Rationale: Dravet Syndrome (DS) is a rare childhood epilepsy disorder with limited therapies available. An important goal at the NINDS contract site for the Epilepsy Therapy Screening Program (ETSP) is to have translatable models which best recapitulate clinical observations. A mouse model of DS was evaluated to characterize spontaneous seizure activity, which aids in optimizing future drug screening experiments.

Methods: Both male and female Scn1a^A1783V/WT mice (n=50) were implanted at P30-P35 with a bipolar electrode over the cortex and a ground electrode over the cerebellum. Mice recovered for 14 days and then were tethered for 24h/day, 7d/week video-EEG recording. Electrographic seizures were defined as sharp-wave discharges, with amplitudes at least 2x the height of baseline and lasting more than 5 seconds, followed by post-ictal depression. A cluster was defined as one or more seizures per day for at least 3 days and at least 5 seizures in a cluster period. Inter-ictal spikes preceding seizures were defined as brief paroxysmal electrographic discharges at least two times the baseline values. Inter-ictal spike frequencies were calculated as the number of spikes present in the two minutes prior to a seizure. Data is presented as mean ± SD.

Results: Scn1a^A1783V/WT mice have on average, 0.9 ± 0.7 seizures per day, with males exhibiting significantly higher seizure frequency as compared to females. Increases in inter-ictal spiking prior to seizure onset and clustering of seizures were observed during data analysis. A randomly selected subset of seizures (n=150) reveals that approximately 76% of seizures are preceded by increases in inter-ictal spiking (6.7 ± 4.8 spikes/min). We calculated the inter-seizure event and found that 77.3% of the seizures occurred within 24 hrs of each other, suggesting clustering activity. Further, 29/50 of the recorded mice experienced at least one cluster during the 14-day recording period. On average, each cluster contained 10.3 ± 6.8 seizures. Mice would have at least one seizure a day for 2.6 ± 1.4 consecutive days and would have on average, 4.2 ± 2.8 consecutive days without a seizure.

Conclusions: While Scn1a^A1783V/WT mice have approximately 1 seizure/day, these seizures cluster. Clustering adds complexity when attempting to evaluate the effects of anti-seizure drugs. Thus, large sample sizes may be needed to compensate for cluster-related challenges. Additionally, the interictal spike analysis performed here sets the stage for future work utilizing closed loop strategies in neuromodulation of seizures.

Funding: Please list any funding that was received in support of this abstract.: This project has been funded in whole or in part by federal funds from the National Institute of Neurological Disorders and Stroke, Epilepsy Therapy Screening Program, National Institutes of Health and Department of Health and Human Services, under Contract No. HHSN271201600048C and an American Epilepsy Society Postdoctoral Research Fellowship.