Abstracts

Rationale: The Kv1.1 knockout (KO) mice are a robust model for both temporal lobe epilepsy as well as sudden unexpected death in epilepsy (SUDEP). The epilepsy onset in these mice is around the third postnatal week, with the seizure severity progressively worsening with age until postnatal week 7 where these mice die of SUDEP. Studies have indicated an increased parasympathetic activity and associated bradycardia as possible mechanisms contributing to SUDEP. The hypothalamic neuropeptide orexin is upstream of the parasympathetic activity and regulation. We hypothesize that an excessive stimulation by orexin results in excessive parasympathetic drive and bradyarrhythmias.  In this study, we assessed the cardiac function in young and near SUDEP KO mice and determined whether administration of almorexant, a dual orexin receptor antagonist (DORA) influences the cardiac function in near SUDEP KO mice. Methods: Electrocardiogram (ECG) was recorded from conscious freely moving mice using ECGenie (Mouse Specifics, Boston, MA). The ECG signals were then subjected to time domain analysis to yield 3 cardiac parameters, a) Heart rate, b) R-R interval and c) Root mean square of standard deviation or rmSSD, a measure of short term heart rate variability. We first compared KO and wild-type (WT) littermates at three ages, postnatal day (P)28-36, P37-44 and P45-52 (age close to sudden death). We assessed the cardiac parameters in Kv1.1 KO mice treated with vehicle or with almorexant (100mg/kg, i.p.) at the near SUDEP ages. Results: Comparing the two genotypes across age we found that there were no significant differences in the cardiac parameters at younger age (P28-36). However, the KO mice had a significant decrease in heart rate, along with a significant increase in R-R intervals and the rmSSD values at the older age groups P37-44 (p < 0.05) and P45-52 (p < 0.01). Comparing within group across ages, we found that there is a progressive decrease in heart rate along    with a progressive increase in R-R interval and rmSSD values from younger ages to the near SUDEP ages (P45-52). At ages closer to SUDEP, we also found that in the KO mice, almorexant treatment normalizes the heart rate, duration of R-R interval as well as rmSSD values to WT standard range. In contrast, the vehicle treated KO mice show significantly lower heart rate (p < 0.001) and significantly higher R-R interval (p < 0.001) duration and rmSSD (p < 0.05) values compared to almorexant treated KO mice. Conclusions: Our data collectively indicate that there is an increase in the incidence of bradycardia with age, becoming significantly higher at near SUDEP ages in the Kv1.1 KO mice. Furthermore, orexinergic antagonism normalizes the incidence of bradycardia in the KO mice at near SUDEP ages. This suggests a potential role of the orexinergic system in promoting bradycardia in a mouse model of SUDEP and its relevance as a therapeutic target for future studies in this model. Funding: This work is supported by NIH NINDS NS072179 (KAS) and the Citizens United for Research in Epilepsy (KAS).