Kelsey Paulhus: Leading with the head or heart? Deciphering the specific roles of Kv1.1 in cardiac function, epilepsy, and SUDEP

Mutations in ion channel genes with brain-heart expression patterns have been proposed as risk factors for sudden unexpected death in epilepsy (SUDEP) since they can cause both seizures and lethal cardiac arrythmias. One such gene is Kcna1, which encodes voltage-gated Kv1.1 potassium channel α-subunits. Kcna1 global knockout (KO) mice recapitulate many features of human SUDEP including frequent generalized tonic-clonic seizures that cause cardiorespiratory dysfunction leading to sudden death in about 80% of animals. Neuron-specific Kcna1 conditional KO (cKO) mice also exhibit premature death, epilepsy, and cardiorespiratory dysregulation, but to a lesser degree than global KOs, suggesting that Kv1.1-deficiency in the heart may cause intrinsic cardiac dysfunction that increases risk of mortality. Here we restrict Kv1.1 deficiency to heart tissue using a newly generated Kv1.1 cardiac cKO mouse to elucidate the contribution of Kv1.1 both to overall cardiac electrophysiology and how cardiac-specific deficiency contributes to the cardiac abnormalities and SUDEP risk seen in global KO and neuron-specific cKO mouse models. Our findings indicate that while Kv1.1 plays a functionally significant role in cardiomyocytes, the cardiac and sudden death phenotypes observed in the global KO and neuron-specific cKO mice are largely brain-driven.