# Regulation of extraysynaptic GABA-A receptors in health and disease

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2022 · —

## Abstract

This project is focused on the cellular and molecular changes caused by traumatic brain injury
(TBI), specifically those affecting GABAergic signaling in the hippocampus. Maladaptive changes in
cellular and molecular properties contribute to the cognitive and neuropsychiatric sequelae of TBI, and
epileptic seizures. The chronic cellular and molecular alterations causing dysfunction after TBI, and the
proximal factors triggered by TBI that induce these chronic changes, are incompletely understood.
Microglia, the resident immune cells of the brain, serve beneficial functions in the healthy brain but in
response to injury their actions can be maladaptive, injurious, and magnify the consequences of TBI.
As such, microglia and their inflammatory signaling are candidate factors to trigger pathophysiological
cellular and molecular changes after TBI. Prior work has established that downregulation of
extrasynaptic GABA receptors is a consistent feature of TBI in the hippocampus. Experiments proposed
here will test the hypotheses that: i) attenuation of microglia activation will limit TBI-induced changes
in extrasynaptic GABA receptor expression and function and ii) attenuation of microglia activation will
decrease the incidence of spontaneous seizures after TBI (epileptogenesis).
 Using a combination of patch-clamp electrophysiology and immunohistochemical techniques,
the expression and function of extrasynaptic GABA receptors (both GABAA and GABAB) in hippocampal
neurons will be assessed in a model of severe TBI (controlled cortical impact, CCI). To assess the role
of microglia in these molecular alterations after TBI, a powerful pharmacological tool that dramatically
depletes brain microglia will be used (PLX5622, a CSF1-R inhibitor). PLX5622-treated animals will be
exposed to CCI, allowing the assessment of whether functional molecular alterations after TBI are
dependent on microglia activation. Specifically, the proposed experiments will determine if changes in
extasynaptic GABA receptors after TBI are dependent on microglia activation. As part of this aim, other
areas affected by TBI (thalamus, cerebellum) will be examined for CCI-associated changes in
extrasynaptic GABA receptor function.
 The cellular effects of TBI and outcomes will also be investigated to assess their dependence on
microglia activation. Using the approach of depleting microglia with PLX5622 prior to CCI, the time
course and magnitude of neuronal death after TBI (for all neurons and specific interneuronal subtypes)
will be determined for control and PLX5622-treated animals. Mossy fiber sprouting (the
pathophysiological arborizing response of DGGC axons to injury) is another cellular change that occurs
as a consequence of TBI; mossy fiber sprouting will be quantified and compared between the two
groups. The cellular and molecular changes proposed for study here are all believed to contribute to
epileptogenesis and seizures, but irrespective of these specific cellular/molecular chan...

## Key facts

- **NIH application ID:** 10487823
- **Project number:** 2I01BX002745-06A2
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** Christopher Bruce Ransom
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2015-10-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487823

## Citation

> US National Institutes of Health, RePORTER application 10487823, Regulation of extraysynaptic GABA-A receptors in health and disease (2I01BX002745-06A2). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10487823. Licensed CC0.

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