Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in young and otherwise healthy patients with epilepsy. Cardiac arrhythmias, respiratory abnormalities, or a combination of both have been postulated in the causation of SUDEP. Voltage-gated Kv1.1 channels, encoded by the Kcna1 gene, conduct a critical potassium current in neurons that prevents hyper-excitability. Mice lacking the Kcna1 gene (Kcna1–/–) recapitulate critical aspects of SUDEP, including frequent generalized seizures, autonomic instability, cardiac dysfunction, and premature death, but seizure-related respiratory dysfunction has never been investigated. Methods: Unrestrained whole body plethysmography recordings were performed to measure breathing in conscious, unanesthetized, and unrestrained mice to test the hypothesis that Kcna1–/– mice exhibit seizure-related respiratory abnormalities that predispose them to SUDEP. A subset of animals was also implanted with electrodes for simultaneous recording of electroencephalography (EEG), electrocardiography (ECG), and electromyography (EMG) to measure the interaction between seizures, respiration, cardiac function, and sleep. Results: During interictal periods, Kcna1–/– animals (n=9) exhibited breathing rates, tidal volumes, and minute ventilation similar to wildtype (WT) littermate controls (n=7). However, Kcna1–/– mice exhibited ~85% reduction in interictal apnea frequency (PKcna1–/– mice, suggesting the absence of postsigh apneas in Kcna1–/– mice is not due to defects in sigh generation or morphology. Postsigh apneas tend to occur predominantly during non-rapid eye movement (NREM) sleep, but normalizing postsigh apnea frequency to time spent in NREM, which is reduced in Kcna1–/– mice, does not appear to account for their drastic decrease in apnea occurrence. Analysis of interictal respiratory variability, calculated as the coefficient of variation (CV), revealed stable breath-to-breath intervals in WT mice but a 3-fold increase in variability in Kcna1–/– mice (PKcna1–/– mice exhibited malignant respiratory abnormalities characterized by a pattern of hyperpnea transitioning to intermittent ataxic or apneic breathing, depending on seizure severity. Studies have also been undertaken to examine the relationship between seizure-associated respiratory and cardiac dysfunction to determine which is the primary driver of SUDEP in this model. Conclusions: The combination of decreased apnea frequency and increased respiratory variability in Kcna1–/– mice suggests that the Kcna1 gene plays an important and previously unrecognized role in basal respiratory physiology. The seizure-related respiratory impairment in Kcna1–/– mice could potentially exacerbate or evoke ictal cardiac arrhythmias and predispose the animals to SUDEP. Funding: This work was supported by grants from Citizens United for Research in Epilepsy, the National Institutes of Health (R00HL107641, R01NS100954), and a Louisiana State University Ike Muslow Predoctoral Fellowship.