# Neurocardiac mechanisms of epilepsy with high risk of SUDEP

> **NIH NIH R01** · SOUTHERN METHODIST UNIVERSITY · 2020 · $323,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Our long-term goal is to understand how gene mutations can cause epilepsy with cardiorespiratory
comorbidities that contribute to risk of sudden unexpected death in epilepsy (SUDEP). People with epilepsy
are 24 times more likely than the general population to die suddenly for unknown pathological reasons; these
deaths are classified as SUDEP and represent the leading cause of epilepsy-related mortality. SUDEP is
hypothesized to result from seizure-driven cardiorespiratory dysfunction that culminates in death. This proposal
investigates the contribution of Kcna1 gene deletion to epilepsy, cardiac dysfunction, and SUDEP by using Cre
recombinase-mediated conditional knockout models. Kcna1, a human epilepsy gene associated with SUDEP
risk in patients, encodes predominantly-axonal Kv1.1 voltage-gated potassium channel α-subunits that are
highly expressed in brain where they act to dampen neuronal excitability. Although the epilepsy phenotype of
Kcna1-null mice has been studied extensively, the mechanisms and anatomical substrates responsible for their
seizures, cardiac dysfunction and sudden death are poorly understood. In addition, new preliminary data
reveals that Kcna1 is expressed in cardiomyocytes as well as brain; therefore, Kv1.1-deficiency in either organ
could be sufficient to mediate cardiac arrhythmias and death.
 Utilizing a newly developed floxed Kcna1 mouse allele, the goal of this project is to test the hypotheses
that brain region-specific Kv1.1-deficiency is sufficient to cause the epilepsy, cardiac phenotypes, and SUDEP
observed in Kcna1-null mice and that the Kv1.1-deficient heart provides a permissive substrate for seizure-
related cardiac abnormalities. Aim 1 examines neurocardiac effects of neuron-, corticolimbic-, and hindbrain-
specific Kcna1 gene deletion. Aim 2 investigates cardiac dysfunction due to cardiac-specific Kcna1 gene
deletion, as well as intrinsic dysfunction in denervated isolated hearts from global KOs. Aim 3 uses kainate-
induced seizures in cardiac-specific cKOs to test whether Kv1.1-deficient hearts are inherently more prone to
seizure-related functional and cardiac abnormalities. This research applies an innovative genetic approach to
the study of brain-heart interactions in epilepsy by exploiting newly developed transgenic mouse models of
SUDEP. These models allow us to identify previously unrecognized brain networks important for SUDEP
pathophysiology and neurocardiac control, establishing them as candidate therapeutic targets for future
studies. Furthermore, this study will improve our understanding of Kcna1 gene function and its role in human
neurological and cardiac diseases.

## Key facts

- **NIH application ID:** 9898482
- **Project number:** 5R01NS099188-05
- **Recipient organization:** SOUTHERN METHODIST UNIVERSITY
- **Principal Investigator:** Albert E Glasscock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $323,750
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898482

## Citation

> US National Institutes of Health, RePORTER application 9898482, Neurocardiac mechanisms of epilepsy with high risk of SUDEP (5R01NS099188-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9898482. Licensed CC0.

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