Cardiorespiratory profiling reveals primary breathing dysfunction in Kcna1-null mice: Implications for sudden unexpected death in epilepsy

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality, but the relative importance of underlying cardiac and respiratory mechanisms remains unclear. To illuminate the interactions between seizures, respiration, cardiac function, and sleep that contribute to SUDEP risk, here we developed a mouse epilepsy monitoring unit (EMU) to simultaneously record video, electroencephalography (EEG), electromyography (EMG), plethysmography, and electrocardiography (ECG) in a commonly used genetic model of SUDEP, the Kcna1 knockout (Kcna1−/−) mouse. During interictal periods, Kcna1−/− mice exhibited an abnormal absence of post-sigh apneas and a 3-fold increase in respiratory variability. During spontaneous convulsive seizures, Kcna1−/− mice displayed an array of aberrant breathing patterns that always preceded cardiac abnormalities. These findings support respiratory dysfunction as a primary risk factor for susceptibility to deleterious cardiorespiratory sequelae in epilepsy and reveal a new role for Kcna1-encoded Kv1.1 channels in the regulation of basal respiratory physiology.