# Chemogenetic analysis of ethanol's selectivity  for GABAA receptor populations

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2020 · $186,784

## Abstract

Project Description. GABAA receptor mediated inhibition sculpts neuronal activity, plays key roles in mood
and cognition, and is a target of important drugs including ethanol. Major classes of GABAA receptors are
defined by γ vs. δ subunit presence, but the relative contributions of these two receptor classes to inhibition
and to ethanol effects remain unclear. Classically, γ populations mediate phasic inhibition, while δ populations
mediate tonic inhibition. A recurring hypothesis is that ethanol at low concentrations selectively potentiates
GABA actions at δ receptors. However, this idea has remained controversial and unresolved. Environmental
factors including other subunits and post-translational modifications complicate efforts to test the hypothesis
rigorously. A key barrier has been the inability to isolate the two receptor populations in native cells without
complications arising from genetic manipulations associated with previous studies (e.g., compensation for
genetic deletion). Pharmacological isolation of γ and δ receptors would allow direct study of ethanol
selectivity with unprecedented resolution and rigor. We approached this issue through a knock-
in/chemogenetic strategy. We developed two knock-in mouse lines harboring picrotoxin resistance in the
endogenous δ or γ subunit respectively. Proof-of-principle experiments in hippocampal dentate granule
neurons have demonstrated the ability to isolate the respective receptor populations and have led to the
hypothesis that δ may play a larger than expected role in phasic inhibition. We will first test the generality of
this conclusion by repeating the evaluation in two additional cell types proposed to be critical for acute ethanol
effects: medium spiny neurons of the nucleus accumbens and cerebellar granule neurons. We then proceed to
test the hypothesis that δ receptors are selectively sensitive to low ethanol concentrations, compared with γ
receptors and with receptors devoid of either δ or γ. Conventional inducible knockouts are used to validate
results. Our experiments will help explain the acute intoxicating effects of ethanol, and success of our
exploratory studies would also prompt future studies to explore chronic effects of ethanol, for which GABAA
receptor populations have also been implicated.

## Key facts

- **NIH application ID:** 9872962
- **Project number:** 5R21AA026753-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** STEVEN J MENNERICK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $186,784
- **Award type:** 5
- **Project period:** 2019-02-15 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872962

## Citation

> US National Institutes of Health, RePORTER application 9872962, Chemogenetic analysis of ethanol's selectivity  for GABAA receptor populations (5R21AA026753-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9872962. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*