# Changes in the Ionic Basis of GABAergic Inhibition that Contribute to Post-Traumatic Epilepsy

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $1,252,782

## Abstract

Brain injury is a common cause of medically intractable epilepsy. Because we do not understand the
underlying pathophysiology, we can’t reduce the burden of medical intractability. The overarching
goal of this research program is to exploit a recently developed large animal gyrencephalic model of
neocortical post-traumatic epilepsy (PTE) to elucidate a mechanism of neocortical epileptogenesis:
chronic compromise of the ionic basis for GABA-mediated inhibition. Disinhibition is a fundamental
element of ictogenesis, but thus far we have not found the mechanism of disinhibition in chronic
epilepsy. There are two salient clues: first, anticonvulsants that increase GABA conductance often do
not ameliorate PTE; and second, studies in human intractable epilepsy have found a positive,
disinhibitory shift in the reversal potential for GABAA receptor-mediated membrane currents (EGABA).
Here we will test the hypothesis that glial reconstruction of the brain’s extracellular matrix after injury
results in increased displacement of extracellular chloride (Cl-o) by the sulfate moieties of the
proteoglycans that comprise the new matrix. To test this hypothesis, we will employ a large-animal
PTE model in which local epileptogenesis occurs after well-characterized neocortical injury (Project 1
and Large Animal Core). This localization of epileptogenesis is critical for correlation of changes in Cl-o,
network structure, and epilepsy. In this injured neocortical area, we will use longitudinal 2-photon in
vivo calcium imaging to test for the network changes expected from disinhibition (Project 2 and
Microscopy Core). In the injured neocortical area, we will use 2-photon Fluorescence Lifetime Imaging
(FLIM) and newly-synthesized Cl- indicators to test for changes in the local Cl-o and intracellular chloride
(Cl-i ) that would drive disinhibition by depolarizing EGABA and reducing the efficacy of shunting inhibition
(Project 3). The 3 projects have a common third aim: to correlate epileptogenesis (Project 1) with
network disinhibition (Project 2) that are associated with chronic changes in Cl-o and Cl-i (Project 3).
Together, these Projects and Cores will test a novel mechanism of epileptogenesis and medical
intractability that could be ameliorated by short-term inhibition of the disassembly of the brain’s
extracellular matrix at the time of injury using MMP inhibitors whose efficacy will be screened in Project
3, Aim 2.

## Key facts

- **NIH application ID:** 10896220
- **Project number:** 5P01NS127769-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Kevin J. Staley
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,252,782
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896220

## Citation

> US National Institutes of Health, RePORTER application 10896220, Changes in the Ionic Basis of GABAergic Inhibition that Contribute to Post-Traumatic Epilepsy (5P01NS127769-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10896220. Licensed CC0.

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