Abstracts

Rationale: The underlying mechanisms of sudden unexpected death in epilepsy (SUDEP) are not yet understood, but the leading hypothesis suggests that seizures propagate dangerous signals to the heart and lungs leading to cardiorespiratory collapse and death. The heart and lungs are primarily under the control of the autonomic nervous system (ANS); thus, it is likely the ANS plays a pathological role. Classical ANS circuitry resides in the brainstem, with upstream influences in forebrain structures. Our lab has used the preclinical global Kv1.1 deficiency mouse model to study SUDEP related mechanisms because this model recapitulates many vital human phenotypes, but how specific regions of the ANS contribute to these important phenotypes has never been studied. This project studies the unique brainstem-specific contributions to cardiorespiratory dysfunction and seizure related mortality seen in our preclinical mouse model which may be related to SUDEP mechanisms.

Methods: We utilized a novel conditional knockout (cKO) mouse model to delete Kcna1 (encoding Kv1.1) in brainstem nuclei. We crossed mice carrying Phox2b-Cre with mice carrying floxed Kcna1 to generate brainstem-specific cKO mice and controls (n= 4-9/genotype). We measured lifespan up to 100 days as a measure of premature mortality. We used simultaneous electroencephalogram- electrocardiogram-plethysmography (EEG-ECG-pleth) recordings to study spontaneous seizure and cardiorespiratory phenotypes. Finally, we induced seizures in these mice using the chemical convulsant flurothyl to measure seizure susceptibility and seizure-related mortality. Statistics were run on GraphPad, and significance was reached if P< 0.05.