Respiratory Abnormalities in the Kcna1-Null Mouse Model of Sudden Unexpected Death in Epilepsy

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in young and otherwise healthy patients with epilepsy, and sudden unexpected death is at least 20 times more common in epilepsy patients than the general population. 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 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. Here, we used unrestrained whole body plethysmography recordings of conscious, unanesthetized mice to test the hypothesis that Kcna1-null mice exhibit seizure-related respiratory abnormalities that predispose the animals to SUDEP. In baseline measurements of respiratory function, we found that null animals exhibited similar breathing rates, tidal volumes, and minute volumes compared to wild type littermate controls. However, null mice exhibited an 85% reduction in apnea frequency suggesting the Kcna1 gene may be important for basal respiratory physiology. Specifically, Kcna1-null mice showed a drastic reduction in the number of type 1 post-sigh apneas despite exhibiting a normal incidence of sighs. In addition, during seizures, null mice exhibited malignant respiratory abnormalities characterized by a pattern of hyperpnea transitioning to intermittent ataxic or apneic breathing, depending on seizure severity. This seizure-related respiratory impairment could potentially exacerbate or evoke ictal cardiac arrhythmias and predispose the animals to SUDEP. Future work will define the sequence of respiratory and cardiac events during seizures in these mice to determine whether respiratory dysfunction occurs primary or secondary to arrhythmias.