# Serotonergic network mechanisms in postictal generalized EEG suppression

> **NIH NIH F31** · UNIVERSITY OF IOWA · 2020 · $31,205

## Abstract

Project Summary
One in twenty-six Americans will develop epilepsy during their lifetime. Unfortunately, one-third of epilepsy
patients will not achieve seizure freedom with conventional therapies. These patients are at greatest risk for
sudden unexpected death in epilepsy (SUDEP), the leading cause of death in patients with refractory epilepsy.
While the exact etiology of SUDEP is unknown, it is thought that cardiorespiratory dysfunction and arousal
impairment are involved. Suppression of EEG activity following a seizure, or post-ictal generalized EEG
suppression (PGES), may correlate with SUDEP risk. The origin of PGES is unknown, but during PGES
patients experience stupor and unresponsiveness. Serotonin (5-HT) is broadly implicated in SUDEP due to its
role breathing, sleep/wakefulness, and arousal. The dorsal raphe nucleus (DRN) is a key source of 5-HT
projections. DRN 5-HT activity is depressed by seizures. We hypothesize PGES may represent an
electrographic marker of impaired arousal consequent to seizure-induced DRN dysregulation. Our preliminary
data in mice indicate that systemic application of a selective serotonin reuptake inhibitor (SSRI) or direct
chemical or optogenetic stimulation of DRN 5-HT neurons prior to an induced seizure shortens PGES duration.
However, the specific network and receptor mechanisms underlying PGES are unknown. Our objective is to
identify a DRN network and 5-HT receptor mechanism that could be manipulated to reduce PGES and prevent
SUDEP. A potential downstream target is the pedunculopontine tegmental nucleus (PPT), a pontine region
involved in sleep-wake regulation, attention, EEG regulation, and arousal. Seizure-induced dysregulation of 5-
HT signaling may interfere with subcortical arousal networks, such as those involving the PPT, and produce
PGES. In Aim 1, to determine a role for a DRN  PPT circuit in PGES, we will optogenetically stimulate and
inhibit DRN 5-HT terminals in the PPT prior to seizures induced by amygdala stimulation in amygdala kindled
mice during wake/NREM/REM and observe changes in PGES duration. Several 5-HT receptors have been
implicated in SUDEP and may be found on cholinergic neurons in the PPT. In Aim 2, we will utilize
immunolabeling-enabled three-dimensional imaging of solvent-cleared organs, RNAscope fluorescent in situ
hybridization, and immunohistochemistry to determine the identity of PPT neurons and 5-HT receptors
contacted by DRN 5-HT terminals. Then we will administer intracranial 5-HT antagonists into the PPT with or
without a selective serotonin reuptake inhibitory onboard, induce an amygdala-kindled seizure, and observe
effects on PGES. Participation in the proposed training plan and completion of the proposed experiments will
advance the applicant’s neuroscience training. It will also elucidate the DRN-PPT circuit and determine its role
in PGES. By manipulating 5-HT circuitry, we may discover ways to eliminate PGES and consequentially
prevent death in high risk epilepsy...

## Key facts

- **NIH application ID:** 9989421
- **Project number:** 1F31NS113479-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Alexandra Petrucci
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,205
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989421

## Citation

> US National Institutes of Health, RePORTER application 9989421, Serotonergic network mechanisms in postictal generalized EEG suppression (1F31NS113479-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9989421. Licensed CC0.

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