Excitability mechanisms of neurocardiac regulation

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The proposed research examines the molecular mechanisms that contribute to neurocardiac dysfunction in mouse models of epilepsy and sudden unexplained death in epilepsy (SUDEP). People with epilepsy are 24 times more likely than the general population to die suddenly for unexplained pathological reasons; therefore, these deaths are classified as SUDEP. This proposal investigates the contribution of parasympathetic neurotransmission to potentially lethal heart arrhythmias in two different epilepsy mouse models of brain-driven cardiac dysfunction linked to SUDEP: 1) a Kcna1 potassium channel knockout mouse model, which exhibits cardiac defects despite minimal cardiac expression; and 2) a Kcnq1 potassium channel missense mutation mouse model, which exhibits cardiac defects associated with co-expression in brain and heart. In Aim 1, vagotomy is used in conjunction with simultaneous video electroencephalography- electrocardiography (EEG-ECG) to assess the effect of parasympathetic neurotransmission on cardiac dysfunction and premature death in Kcna1-null mice. In Aim 2, Kcna1-null mice are administered drugs that selectively activate the vagus nerve to determine whether stimulation of parasympathetic neurotransmission increases cardiac dysfunction in Kcna1-null mice as measured by EEG-ECG. In Aim 3, vagus nerve and intracardiac electrophysiology are used to determine if the lack of Kv1.1 channels affects vagal excitability or vulnerability to inducible cardiac arrhythmias. In Aim 4, immunohistochemistry is used to image immediate early gene expression to generate a map of autonomic brain centers activated by seizures in Kcna1-null mice. In Aim 5, the same battery of tests described in Aims 1-4 for Kcna1-null mice will be used to determine if cardiac defects in Kcnq1 mouse models of brain-heart potassium channel dysfunction have an underlying neural contribution and show mechanistic similarities with Kcna1 models. Aims 1-4 will be completed during the K99 phase and Aim 5 during the R00 phase. The candidate for this career development award is pursuing a career as an independent investigator in neurocardiology, addressing research questions related to the brain-heart interaction. Of particular interest is the genetic basis of excitability disorders, especially epilepsy, and how gene mutations can cause excitability defects in multiple tissues at once, such as the brain and heart, providing a novel explanation for the prevalence of disease comorbidities. For career development activities during the K99 phase, the candidate will: 1) expand his experimental skillset; 2) increase his brain-heart knowledge-base by participating in scientific meetings; and 3) enhance his leadership/teaching skills by mentoring students and leading seminars and journal clubs. The candidate will also receive training in the responsible conduct of research. The candidate's institution, Baylor College of Medicine, is well-suited for the proposed research and training goals because of the breadth of experimental resources it offers and the number of accessible experts in neurology and cardiology.