# Molecular control of aberrant adult-born granule cells in epilepsy

> **NIH NIH R01** · UNIVERSITY OF TEXAS SAN ANTONIO · 2024 · $411,796

## Abstract

Project Summary/Abstract:
The latent period after a severe brain insult such as traumatic brain injury or status epilepticus, and before the
onset of spontaneous recurrent seizures, is characterized by changes in adult hippocampal neurogenesis.
Profound morphological changes, including hilar ectopic granule cells and abnormal dendritic development
(e.g., hilar basal dendrites) is observed, therefore raising the question whether seizure- induced neurogenesis
is epileptogenic. Our past work of ablating adult neurogenesis before or after acute seizures has shown a pro-
epileptic role of new neurons, however existing ablation strategies in animal models have all suffered from an
inability to decipher the mechanisms that promote aberrant adult-born granule cells (abGCs) because the cells
are removed from the circuit. In this revised R01 application, we will capitalize on recently published work from
our laboratory demonstrating that activity in immature abGCs regulates Ca2+ and gene expression which is
necessary and sufficient for the production of aberrant abGCs and disruption of the hippocampal circuitry
leading to epilepsy. We propose work to determine the mechanisms that promote aberrant neurogenesis,
focusing on the genes and signaling pathways that drive aberrant abGCs as well as identifying the neuronal
inputs to the aberrant abGCs. Because our past work has always been in the pilocarpine model of mesial
temporal lobe epilepsy, we will expand these studies to address the role of aberrant abGCs in a non-status
model, such as epilepsy that occurs after controlled cortical impact injury. In Aim 1, we will demonstrate that
hM4Di-regulated gene expression in abGCs offers a new way to manipulate potential aberrant gene regulatory
pathways and define the functional role of our top 2 candidate genes – Timp3 and Rrm2 - identified in RNA-
sequencing analysis. In Aim 2, we will complement the work in Aim 1 using hM4Di in the pilocarpine model and
identify the hM3Dq activated genes and neuronal inputs associated with aberrant abGCs in wild-type mice. In
Aim 3, we will ablate or silence abGCs after controlled cortical impact injury and evaluate the impact on the
development of chronic seizures. Together these studies are expected to provide a greater understanding of
the mechanisms that promote aberrant abGC maturation, which may offer new strategies to specifically target
abnormal new neurons while sparing healthy neurons. These studies would be broadly impactful in a variety of
neurological disorders including epilepsy.

## Key facts

- **NIH application ID:** 10877035
- **Project number:** 5R01NS124855-02
- **Recipient organization:** UNIVERSITY OF TEXAS SAN ANTONIO
- **Principal Investigator:** Jenny Hsieh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $411,796
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877035

## Citation

> US National Institutes of Health, RePORTER application 10877035, Molecular control of aberrant adult-born granule cells in epilepsy (5R01NS124855-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877035. Licensed CC0.

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