# Molecular Component - Contet

> **NIH NIH P60** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $222,122

## Abstract

SUMMARY
The overarching working model of The Scripps Research Institute Alcohol Research Center (TSRI-ARC) is that
the infralimbic subdivision of the medial prefrontal cortex (mPFC) represents a critical hub for the dysregulation
of brain network activity by chronic intermittent ethanol (CIE) exposure, driven in part by inputs from the
hypothalamus and impairing top-down control over the central nucleus of the amygdala (CeA). Within this
framework, the Molecular Component, led by Drs. Contet and Dunning, will test the hypothesis that reduced
abundance of metabotropic glutamate receptor 3 (GRM3) in mPFC astrocytes contributes to behavioral
phenotypes of alcohol dependence in mice by maintaining a local hyperglutamatergic tone that elevates the
inhibitory input of local interneurons onto pyramidal neurons projecting to the CeA. This hypothesis is supported
by results generated during the previous funding period, which revealed a long-lasting impact of CIE-induced
excessive alcohol drinking on the abundance of astrocytic markers, with GRM3 reaching proteome-wide
significance, in both prelimbic and infralimbic mPFC samples. GRM3 is strongly enriched in astrocytes where it
controls glutamate uptake, but it can also regulate synaptic transmission and plasticity in neurons. Specific Aim 1
of this project will thus be to determine whether the GRM3 abundance reduction detected in bulk proteomes
stems from a reduction in astrocytes vs. neurons. To do this, we will leverage state-of-the-art quantitative mass
spectrometry from metabolically labeled brain samples to tease apart protein abundance changes in different
cell types. We anticipate that CIE-induced mPFC GRM3 deficiency will be specific to astrocytes and will be
associated with reduced abundance of glutamate transporters. We will also probe a potential role of CRF1
receptor signaling in this effect. We will then test the hypotheses that reduced GRM3 abundance is both
necessary (Specific Aim 2) and sufficient (Specific Aim 3) to produce the behavioral phenotypes of CIE
withdrawal in mice with a history of chronic excessive alcohol drinking, using gene expression manipulations
targeted to mPFC astrocytes. Analyzing the consequences of GRM3 overexpression and knockdown on cell
type-specific proteomes, extracellular glutamate levels, and synaptic transmission will provide mechanistic
insights into how these behavioral outcomes might be generated. Furthermore, Specific Aim 2 will include a
translational approach to rescue GRM3 signaling via inhibition of glutamate carboxypeptidase II (GCPII).
Altogether, this project is anticipated to establish the relevance of astrocytic GRM3 as an important regulator of
glutamate homeostasis in the mPFC that can be targeted to reduce excessive alcohol drinking. It will benefit
from the expertise and resources provided by the Neuroproteomics and Animal Models Cores and will interact
both conceptually and experimentally with the four other TSRI-ARC Research Components.

## Key facts

- **NIH application ID:** 10526266
- **Project number:** 2P60AA006420-40
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Candice Contet
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $222,122
- **Award type:** 2
- **Project period:** 1983-12-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526266

## Citation

> US National Institutes of Health, RePORTER application 10526266, Molecular Component - Contet (2P60AA006420-40). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10526266. Licensed CC0.

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