Sunday, December 22, 2024
12/22/2024
Our long-term goal is to understand how channelopathies can cause epilepsy with cardiorespiratory comorbidities and susceptibility to sudden unexpected death in epilepsy (SUDEP), the leading cause of epilepsy-related mortality. Deaths are classified as SUDEP when people with epilepsy die suddenly for unknown pathological reasons. SUDEP is hypothesized to result from seizure-related cardiorespiratory dysfunction that culminates in death. However, the relative importance and interrelationship of cardiac and respiratory factors underlying SUDEP is unclear, posing a significant barrier to progress in the field. Mutations in ion channel genes with brain-heart expression patterns, such as the Kcna1 gene, have been proposed to be a molecular cause of seizure-related cardiac arrhythmias underlying SUDEP. Kcna1, a human epilepsy gene associated with increased SUDEP risk in patients, encodes voltage-gated Kv1.1 potassium channel α-subunits that are expressed in neurons and cardiomyocytes where they act to control action potential firing properties. The Kcna1 knockout (KO) mouse is an often utilized model of SUDEP since it recapitulates key aspects of the human condition, including tonic-clonic seizures, ictal bradycardia, and premature death. Whereas the epilepsy and cardiac phenotypes of Kcna1 KO mice have been studied extensively in relation to SUDEP, a possible contribution by respiratory dysfunction has not been explored. In preliminary experiments, we used plethysmography to identify several types of breathing abnormalities in Kcna1 KO mice. During spontaneous seizures, KO mice exhibited apneas, suggesting respiratory dysfunction may be the primary factor contributing to their sudden death. During interictal periods, they exhibited alterations in post-sigh apnea frequency and respiratory variability suggesting a role for Kv1.1 in maintaining normal respiratory physiology. The goal of this project is to test the hypothesis that Kv1.1 channels are required for normal respiratory physiology and that their absence leads to respiratory abnormalities that contribute to SUDEP risk. Aim 1 will test the hypothesis that respiratory dysfunction precedes bradycardia during seizures in Kcna1 KO mice. Aim 2 will test the hypothesis that sleep-wake status contributes to the occurrence of interictal and ictal apneas in Kcna1 KO mice. To acquire in vivo biosignals in aims 1 and 2, we have established a novel, state-of-the-art mouse epilepsy monitoring unit to record simultaneous brain-heart-muscle-respiratory activity. Aim 3 will use immunohistochemistry to test the hypothesis that Kv1.1 channels are expressed in brainstem respiratory networks and that their deficiency leads to seizure-related damage. This research will illuminate the crossroads between respiratory and cardiac mechanisms underlying SUDEP, while elucidating a novel role for Kv1.1 channels in regulating basal respiratory physiology. The results of this study will impact the development of future preventative measures for SUDEP by identifying new cardiorespiratory strategies for intervention.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).