Abstracts

Rationale: While not fully understood, the leading hypothesis for sudden unexpected death in epilepsy (SUDEP) suggests dysfunction between the brain, 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 important 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 contributions of corticolimbic (CL) and brainstem (BS) specific circuitry to cardiorespiratory dysfunction and seizure related mortality seen in our preclinical mouse model which may be related to SUDEP mechanisms.

Methods: We utilized conditional knockout (cKO) mouse models to selectively delete Kcna1 (encoding Kv1.1) in corticolimbic or brainstem nuclei. We crossed mice carrying Emx1-Cre or Phox2b-Cre with mice carrying floxed Kcna1 to generate corticolimbic (CL) or brainstem (BS) specific cKO mice, respectively, 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 (e.g., heart rate, heart rate variability, apneas, respiratory rate, etc). Finally, we induced seizures in these mice using the chemical convulsant flurothyl to measure seizure susceptibility and seizure-related mortality. Statistics were analyzed with GraphPad Prism software, and P< 0.05 used for significance.