# Role of hippocampal interneurons in aberrant neurogenesis and epilepsy after traumatic brain injury

> **NIH VA IK2** · PORTLAND VA MEDICAL CENTER · 2024 · —

## Abstract

Abstract
Post-traumatic epilepsy (PTE) can result from combat-related traumatic brain injury
(TBI), a well-documented phenomenon that has caused substantial neurologic disease
in Veterans, most recently in relation to conflicts in the Middle East (>350,000 cases of
combat-related TBI since 2000). Unfortunately, current treatments for PTE are of limited
efficacy, and thus many Veterans with PTE do not have effective seizure control. PTE
often manifests as a form of temporal lobe epilepsy, which involves cellular and
functional circuit alterations in the hippocampal region of the brain. In the healthy
hippocampus, dentate granule cells (DGCs) form a principal cell layer that prevent
hyperexcitability through their low firing frequency and relatively hyperpolarized resting
membrane potentials. Additionally, the dentate gyrus is a region of ongoing
neurogenesis, in which new DGCs are generated throughout adult life and integrate into
the existing circuitry, in a process critical to learning and memory. TBI and epilepsy
involve the aberrant maturation and integration of adult-born DGCs in the hippocampus,
which is thought to disrupt hippocampal function and increase brain excitability leading
to seizures. In this region, parvalbumin-positive (PV+) inhibitory basket interneurons not
only mediate feed-forward inhibition, but release the neurotransmitter GABA onto
immature granule cells and neuroblasts, which modulates circuit integration of these
cells as they mature in the hippocampus. Although these interneurons are preserved in
many animal models of epilepsy, PV+ basket cells undergo numerous functional and
network changes, including reduced excitatory input, increased output failure, and
presynaptic calcium channel dysfunction. Prior hypotheses have examined the potential
direct contribution of PV+ cell dysfunction to hippocampal hyperexcitability after TBI. In
this proposal, I hypothesize that dysfunction of PV+ basket cells after TBI contributes
indirectly to hyperexcitability, by driving aberrant maturation and integration of adult-born
DGCs. I will investigate how TBI impacts PV+ basket cell function at the cellular and
network level, how this dysfunction influences development and integration of adult-born
DGCs, and whether changes in PV-cell specific microcircuit structure and function drive
whole animal seizure susceptibility following TBI. This proposal will use transgenic mice
to selectively target the PV+ basket cell population for expression of calcium indicators,
excitatory channelrhodopsins, or specific synthetic receptors to measure PV-cell specific
network activity after TBI, as well as the functional outputs of these cells. I will also
combine these techniques with retrovirus-mediated labeling of adult-born DGCs, to
determine whether changes in post-TBI PV+ basket cell function alter the maturation,
integration, or circuit dynamics of adult-born DGCs after TBI. Finally, I will manipulate
activity of the PV+ basket cells in vivo to as...

## Key facts

- **NIH application ID:** 10767931
- **Project number:** 5IK2BX005761-02
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** CORWIN BUTLER
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767931

## Citation

> US National Institutes of Health, RePORTER application 10767931, Role of hippocampal interneurons in aberrant neurogenesis and epilepsy after traumatic brain injury (5IK2BX005761-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10767931. Licensed CC0.

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