# Respiratory mechanisms of epilepsy with high risk of SUDEP

> **NIH NIH R01** · SOUTHERN METHODIST UNIVERSITY · 2021 · $323,750

## Abstract

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 preve...

## Key facts

- **NIH application ID:** 10076864
- **Project number:** 5R01NS100954-06
- **Recipient organization:** SOUTHERN METHODIST UNIVERSITY
- **Principal Investigator:** Albert E Glasscock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $323,750
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076864

## Citation

> US National Institutes of Health, RePORTER application 10076864, Respiratory mechanisms of epilepsy with high risk of SUDEP (5R01NS100954-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10076864. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*