# Progressive seizure-induced cardiorespiratory dysfunction in a novel mutant rat model of seizure disorder

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $580,601

## Abstract

Project Summary
More than 50 million people suffer from epilepsy globally. Current anti-epileptic drugs (AEDs) cannot prevent
seizures in ~30% of these patients, leading to uncontrolled or refractory epilepsy. Unfortunately, these patients
are at extreme risk of Sudden Unexpected Death in Epilepsy (SUDEP), which is the leading cause of death in
this cohort. Based on landmark SUDEP studies, the current hypothesis is that recurrent seizures induce extreme
cardiorespiratory suppression and/or failure through negative effects on the neural networks that regulate vital
functions such as breathing, heart rate and blood pressure. However, it remains unclear how repeated seizures
fundamentally affect cardiorespiratory control networks within the brainstem, and by what mechanisms these
vital systems fail in SUDEP. Here we aim to characterize the pathophysiologic consequences of repeated
seizures in a novel rat model with a known mutation in a potassium channel gene (kcnj16; SSkcnj16-/- rats), in
which a specific sound of mild intensity readily and reproducibly causes generalized tonic-clonic seizures
(GTCSs). Sound-induced GTCSs in SSkcnj16-/- rats led to a stereotypic pattern of events similar to that described
in epilepsy patients, including post-ictal generalized EEG suppression and apnea, followed by respiratory rate
(RR) and heart rate (HR) suppression. Repeated seizures (1/day for up to 10 days) led to: 1) augmented post-
ictal suppression of RR and HR, reduced ventilatory responses to hypoxic and hypercapnic challenges, and
unexpected mortality in ~33% of these rats. Brainstem tissue analyses of SSkcnj16-/- rats exposed to repeated
seizures showed evidence of time-dependent increases in inflammation and dysregulation of adenosine (ADO)
and serotonin (5-HT) – two powerful modulators of cardiorespiratory neural networks. Finally, pharmacologically
augmenting 5-HT with an SSRI (fluoxetine) prevented the progressive suppression of post-ictal RR with repeated
seizures. Herein we will test our central hypothesis that repeated seizures cause a progressive brainstem
pathology initiated by neuroinflammation and mediated by ADO and 5-HT dysfunction leading to
cardiorespiratory suppression and/or failure in SUDEP. The proposed studies utilizing this novel mutant rat
model will provide: 1) a comprehensive characterization of the progressive pathophysiological responses to
repeated audiogenic seizures, and sequence of events leading to unexpected death (Aim 1), 2) identified
mechanisms of dysfunction in inflammatory and/or neuromodulatory pathways within critical cardiorespiratory
brainstem nuclei negatively affected by repeated seizures (Aim 2), and 3) interventions that functionally test our
hypothesis by blocking neuroinflammation or modulating ADO or 5-HT system activity on the backdrop of
repeated seizures (Aim 3). We will utilize a combination of established and cutting-edge technologies to provide
unprecedented molecular, cellular and systems-level insig...

## Key facts

- **NIH application ID:** 10396645
- **Project number:** 5R01HL122358-07
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Matthew Robert Hodges
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $580,601
- **Award type:** 5
- **Project period:** 2015-04-17 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396645

## Citation

> US National Institutes of Health, RePORTER application 10396645, Progressive seizure-induced cardiorespiratory dysfunction in a novel mutant rat model of seizure disorder (5R01HL122358-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10396645. Licensed CC0.

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