# Role of adenosinergic inhibition of serotonin neurons in seizure induced respiratory arrest

> **NIH NIH F32** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $76,756

## Abstract

Project Summary
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature death in persons with epilepsy
who do not have satisfactory seizure control. SUDEP results in more years of potential life lost than any other
neurological condition with the exception of stroke. There are no known ways of reliably preventing SUDEP.
Convergent lines of evidence suggest that respiratory dysfunction is a critical component of SUDEP
pathophysiology. There are several potential mechanistic explanations for the respiratory arrest seen in SUDEP.
(1) Serotonin signaling is important for stable breathing and increasing serotonergic tone may be protective
against seizure-induced respiratory arrest. Unfortunately, seizures disrupt serotonergic neurotransmission.
There is a gap in knowledge as to the mechanism responsible for seizure-induced disruption of serotonergic
neurotransmission. (2) Seizures also cause a surge in extracellular adenosine throughout the brain. Increases
in adenosine levels suppress breathing and inhibit neural activity. Excessive adenosine signaling has been
implicated in the respiratory dysfunction seen in SUDEP; however, the mechanism by which adenosine affects
breathing after seizures is unknown. (3) Slow moving (2-5 mm/min) waves of spreading depolarization are
sometimes triggered by seizures. Spreading depolarization transiently inactivates the brain tissue. Under certain
circumstances spreading depolarization can travel into the brainstem where it halts neural activity in nuclei
necessary for cardiorespiratory function and causes death. Brainstem spreading depolarization is a potential
cause of SUDEP. Spreading depolarization also causes an increase in extracellular adenosine. It is not known
whether the increase in adenosine due to spreading depolarization contributes to seizure-induced death. The
goal of this proposal is to integrate the serotonergic, adenosinergic, and spreading depolarization explanations
of SUDEP etiology by testing the central hypothesis that adenosine surging as the result of seizure activity and
spreading depolarization disrupts serotonergic neurotransmission thereby potentiating respiratory failure. In the
first aim, adenosine signaling will be augmented in the serotonergic raphe nuclei during seizures to determine if
this alters respiratory responsiveness to CO2 and the likelihood of respiratory failure. In the second aim,
brainstem spreading depolarization will be induced in mice in which adenosine signaling has been
pharmacologically or genetically altered in the raphe nuclei. The proposed experiments will generate compelling
evidence for or against the hypothesized interaction between serotonin and adenosine while providing the
training in writing, mentorship, and quantitatively rigorous hypothesis-testing necessary for a career in science.

## Key facts

- **NIH application ID:** 10824414
- **Project number:** 5F32NS117792-03
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Benton Scott Purnell
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $76,756
- **Award type:** 5
- **Project period:** 2022-05-23 → 2025-05-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824414

## Citation

> US National Institutes of Health, RePORTER application 10824414, Role of adenosinergic inhibition of serotonin neurons in seizure induced respiratory arrest (5F32NS117792-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10824414. Licensed CC0.

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