# GABA Receptor Plasticity and Tonic Inhibition in Epilepsy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $367,422

## Abstract

Project Summary
Tonic inhibition is a major form of inhibition in the central nervous system (CNS) and could play a key role in
epileptogenesis and seizure generation. Nonsynaptic GABAA receptor (GABAAR) subunits that mediate tonic
inhibition, including the δ subunit, are frequently altered in animal models of lesion-induced epilepsy. However,
it remains unclear whether several of these changes contribute to or limit seizure activity. It becomes
particularly important to understand the functional effects of these changes as new pharmacological agents
that can modify the function of δ subunit-containing receptors are developed. A set of new technologies,
reagents and mice will be used to study the functional effects of altering GABAAR subunit expression in
granule cells of the dentate gyrus which are considered to be major players in seizure generation or
propagation within the hippocampal network. The proposed studies will use Cre recombinase-dependent viral
vectors to express GABAAR δ subunit selectively in granule cells and determine the effects of this alteration on
epileptiform activity within the network in a mouse model of epilepsy. A combination of light and electron
microscopic immunohistochemical methods will be used to evaluate changes in GABAAR subunit expression,
and the functional correlates will be studied with electrophysiological methods, behavioral memory tasks, and
Fos expression as a marker of neuronal activity in vivo. The broad goal of the project is to determine if
increasing nonsynaptic GABAAR subunits in a cell-type selective manner will influence tonic inhibition and
epileptiform activity in a mouse model of epilepsy. Specific Aim 1 will test the hypothesis that transfection of
the δ subunit in dentate granule cells will rescue the decreased expression of this subunit that frequently
occurs in mouse models of epilepsy and, in the process, normalize expression of two related subunits, α4 and
γ2, that are also altered in mouse models of epilepsy. Specific Aim 2 will test the hypothesis that an increase
in δ subunit expression will enhance GABAAR-mediated tonic inhibition in dentate granule cells and reduce
heightened responses of these neurons to perforant path stimulation in seizure-prone mice. Specific Aim 3
will test the hypothesis that increasing δ subunit expression in dentate granule cells will reduce network
hyperexcitability and propagation of epileptiform activity in an animal model of epilepsy, using a novel
hippocampal-entorhinal cortex slice preparation. Specific Aim 4 will test the hypothesis that enhancing δ
subunit expression in dentate granule cells will lead to improved performance on a working memory task in
which pilocarpine-treated mice are normally deficient. The effects of increased δ subunit expression on
granule cell activity in vivo during an elicited seizure will also be determined. Together these studies will
increase our understanding of the effects of altering δ subunit-mediated tonic inhibition...

## Key facts

- **NIH application ID:** 9844078
- **Project number:** 5R01NS075245-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** CAROLYN R HOUSER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $367,422
- **Award type:** 5
- **Project period:** 2012-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844078

## Citation

> US National Institutes of Health, RePORTER application 9844078, GABA Receptor Plasticity and Tonic Inhibition in Epilepsy (5R01NS075245-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9844078. Licensed CC0.

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