# Optogenetics: A tool to probe mechanism and an agent to block TBI-induced epileptogenesis.

> **NIH VA I01** · VA MEDICAL CENTER - LEXINGTON, KY · 2022 · —

## Abstract

Over two million people are treated medically each year in the United States after sustaining a
traumatic brain injury (TBI). Posttraumatic epilepsy (PTE) develops in up to 39% of patients with moderate to
severe, non-penetrating TBI. As with other acquired epilepsies, spontaneous recurrent seizures associated
with PTE develop with a latency (>1 week and up to many years) after the initial injury. This seizure-free period
after TBI represents the period of epileptogenesis, during which the brain undergoes physiological, anatomical,
cellular, and molecular changes leading to a state of chronically increased seizure susceptibility. This delay
between the TBI and development of PTE also represents a period during which strategies might be employed
to inhibit the reactive plasticity in the brain that leads to PTE, but the molecular mechanisms underlying the
epileptogenic process leading to acquired epilepsy are largely unknown and no anti-epileptogenic therapies
have been successfully developed to date. Animal models of posttraumatic epileptogenesis (PTEgenesis) point
to reactive plasticity of hippocampal networks, with alteration in the balance of excitation/inhibition as a driver
of permanent brain changes and the epileptic state. However, the prime molecular and electrophysiological
transformations remain murky.
 The hypothesis to be tested: Post-injury activity and network changes in the hippocampus, induced in
part by alterations in the vesicular neurotransmitter release machinery, are primary drivers of PTEgenesis. The
Specific Aims are to: 1) Use channelrhodopsin-2 (ChR2) to optogenetically drive neural activity and the
process of PTEgenesis by depolarizing specific primary neuronal populations in dentate gyrus (DG). 2) Use
halorhodopsin (NpHR) to retard PTEgenesis, induced using a standard method, by optogenetically inhibiting
neural activity in DG. Proven techniques will be integrated into a new and unique model to detect network and
molecular drivers of PTE and PTEgenesis. Using the controlled cortical impact (CCI) model of TBI, our
proposed studies combine 1) unique microelectrode array electrochemistry (MEA) to monitor real-time
glutamate release and oxygen change as a metric of epileptiform activity; 2) immunohistochemistry to define
changes in specific cell phenotypes; and 3) slice electrophysiology with custom Western blot quantitation of
neurotransmitter release machinery on a novel, optogenetically-modified hippocampal platform.
 Aim 1: Studies will be accomplished by AAV2/5 viral transfection of a ChR2-promotor construct into
hippocampal DG of rats, utilizing optogenetic activation of DG neurons of free-roaming rats after CCI-induced
TBI to enhance PTEgenesis. Extra-cellular glutamate, electrophysiological, immunohistochemical, and
vesicular release biochemical measures will be made on animals at discrete behavioral stages during the
progression of epileptogenesis. Aim 2: Studies will be accomplished by AAV2/5 viral transfection of ...

## Key facts

- **NIH application ID:** 10454876
- **Project number:** 5I01BX004542-04
- **Recipient organization:** VA MEDICAL CENTER - LEXINGTON, KY
- **Principal Investigator:** John T. Slevin
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454876

## Citation

> US National Institutes of Health, RePORTER application 10454876, Optogenetics: A tool to probe mechanism and an agent to block TBI-induced epileptogenesis. (5I01BX004542-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10454876. Licensed CC0.

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