# The neural circuitry of seizure-induced apnea and SUDEP

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $391,638

## Abstract

Sudden Unexpected Death in Epilepsy (SUDEP) accounts for up to 17% of all epilepsy-related deaths, and
50% for those refractory to treatment. There is increasing evidence that apnea (respiratory arrest) is the
primary cause of death from SUDEP. We have shown in a number of mouse models - including PTZ injection,
rapid kindling (prelim. data), and mouse models harboring Scn8a mutations identified from SUDEP patients -
that sudden death is due to seizure-induced apnea (SIA) that occurs during tonic seizures, minutes prior
to terminal asystole. As it pertains to this proposal, we have also made four other important observations:
1) artificial ventilation can prevent death and suppressed cardiac activity does not increase likelihood of fatality;
2) tonic contraction of breathing muscles represents a likely mechanism of SIA; 3) inhibition of cortical seizure
activity does not impact SIA; and 4) inhibition of the inspiratory oscillator does not reduce apnea (prelim. data),
suggesting seizure spread bypasses homeostatic elements of respiratory control circuitry. CENTRAL
HYPOTHESIS: [AIM 1] Increased midbrain and pontine excitability is both necessary and sufficient to
produce SIA, [AIM 2] the parabrachial/kölliker fuse (PB/KF) nucleus in the pons represents a key nodal
point for SIA generation, and [AIM 3] that brainstem nuclei, like the PB/KF and PAG are recruited
specifically during SIA, which we will explore using electrophysiology and genetic mapping. AIM 1: We
have previously used chemogenetics to demonstrate that cortical ictal activity is not required for SIA and we now
propose that hyperexcitability of the pons and midbrain drive SIA and SUDEP. We will use chemogenetics to
inhibit different parts of the brainstem of Scn8a mutant mice to test their necessity for SIA and SUDEP.
Additionally, we will test sufficiency of these regions by selectively expressing an Scn8a mutation that increases
neuronal excitability. Using the rapid kindling model, we will also perform patch clamp recordings to test whether
increased neuronal excitability in these regions occurs concurrently with the development of SIA. AIM 2: The
parabrachial/kölliker fuse nucleus PB/KF in the Pons is a key nodal point for descending forebrain input and
projects past the inspiratory oscillator, and is modulated by the vagus nerve. In this aim, we will photoinhibit the
Foxp2-positive PB/KF neurons to regain normal breathing pattern during SIA, photostimulate P2ry1-positive
vagal afferent nerve fibers to interrupt inspiration during SIA, and determine if PB/KF and Npy2r-positive vagal
neuron photostimulation rescues postictal breathing in our PTZ SUDEP mouse model. AIM 3: We have
demonstrated that tonic seizures with SIA and clonic seizures without SIA can occur in the very same mouse,
both in Scn8a mutant and rapid kindling models (prelim. data) and that certain mid- and hindbrain structures are
activated during SIA. We will determine the neuronal circuitry activated specifically duri...

## Key facts

- **NIH application ID:** 10853007
- **Project number:** 5R01NS133139-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Ian Christopher Wenker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $391,638
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853007

## Citation

> US National Institutes of Health, RePORTER application 10853007, The neural circuitry of seizure-induced apnea and SUDEP (5R01NS133139-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10853007. Licensed CC0.

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