# Mapping serotonergic neuron subtypes protective for seizure-induced neurological and neurobehavioral changes

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2020 · $31,173

## Abstract

Project Summary/Abstract
Repetitive and severe seizures in temporal lobe epilepsy patients cause neuropathological changes in the
brain, such as neurodegeneration, gliosis, and cell death in the hippocampus, which are associated with
cognitive deficits. Studies in rodent models have shown that increasing the extracellular concentration of the
neurotransmitter serotonin through Selective Serotonin Reuptake Inhibitors (SSRIs) is capable of reducing
seizure severity, preventing neuropathological plasticity in the hippocampus, and precluding associated
memory impairments. These findings suggest that serotonin neurons are essential for maintaining normal
resistance to seizures and further that augmenting serotonergic neuronal signaling may be able to prevent
seizures or seizure-induced impairments. However, little is known about the underlying serotonergic circuitry
and responsible serotonin neuronal subtypes, though such discovery could provide a path to more efficient
epilepsy treatments. With this motivation, coupled with recent findings by our lab and others identifying in mice
functionally and molecularly distinct subtypes of serotonergic neurons, we hypothesize that the three major
subtypes of serotonergic neurons that project to the hippocampus do not contribute equally to
regulating seizure susceptibility and post-seizure neuropathological changes. To test this, I will employ
loss- and gain-of-neuron activity experiments in which individually each of these three hippocampal-projecting
subtypes of serotonergic neurons are selectively manipulated in vivo using our labs well-established
intersectional genetic tools, but now within the context of a robust kainic acid-induced seizure model. More
specifically, in Aim 1, I will assess the effects of serotonergic neuron subtype inhibition on seizure progression,
severity, and post-seizure cellular reorganization. In Aim 2, I will assess the extent to which activation of
specific serotonergic neuron subtypes can ameliorate or prevent seizures, seizure-induced cellular
reorganization, and/or seizure-induced memory deficits. Given the genetic tools, mouse models, and expertise
of the lab, along with successful preliminary studies integrating seizure-induction and behavioral and
histopathological readouts, the proposed work is feasible. We have as well engaged experts in epilepsy and
seizure models and mouse neurobehavioral memory assays, further ensuring expeditious completion and
concomitant in depth pre-doctoral training. Results are expected to inform on the basic neurobiology
underlying serotonergic protection from seizures and their sequelae. Coupled with our recent extensive
molecular characterization of these serotonergic neuron subtypes, findings here could inform development of
highly targeted therapeutics for epilepsy.

## Key facts

- **NIH application ID:** 9995589
- **Project number:** 5F31NS108406-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Rebecca Alexis Senft
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,173
- **Award type:** 5
- **Project period:** 2018-09-30 → 2021-08-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995589

## Citation

> US National Institutes of Health, RePORTER application 9995589, Mapping serotonergic neuron subtypes protective for seizure-induced neurological and neurobehavioral changes (5F31NS108406-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9995589. Licensed CC0.

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