# Input specific adaptations to glutamatergic strength and plasticity on PFC PV-INs following ethanol drinking

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $48,974

## Abstract

Project Summary/Abstract:
Although both men and women are affected by alcohol use disorder (AUD), women often progress through
AUD disease milestones faster and experience more severe health consequences than men. One key brain
region associated with AUD is the prefrontal cortex (PFC), a structure associated with deficits in moderating
drinking behaviors. Previous findings from our lab demonstrate that parvalbumin-expressing inhibitory
interneurons (PV-INs), a key subpopulation of GABAergic cells within PFC, display basal sex differences in
membrane physiology and undergo sex-dependent adaptations in synaptic strength following chronic drinking.
In recent years, the metabotropic glutamate (mGlu) receptor subtype 5 has emerged as a promising
therapeutic target for the treatment of AUD. The mGlu5 receptor is highly expressed on PFC PV-INs and has
been implicated in mediating ethanol seeking across several rodent models of AUD. However, limited clinical
success of compounds that inhibit mGlu5 receptors necessitates a more precise understanding of the circuits
and synaptic mechanisms through which mGlu5 receptors regulate drinking behaviors. My preliminary data
suggests that mGlu5 receptors sex-dependently regulate synaptic transmission and endocannabinoid plasticity
onto PFC PV-INs. In this proposal I will use ex vivo slice electrophysiology, viral-mediated optogenetic tools,
and RNAscope to test the hypothesis that distinct excitatory inputs onto PV-INs are regulated by mGlu5
receptor signaling, and that chronic drinking functionally alters these inputs and mGlu5 receptor
function. This proposal will specifically assess glutamatergic afferents from the basolateral amygdala (BLA)
and mediodorsal thalamus (MDT), which preferentially target PV-INs to drive robust feedforward inhibition in
the PFC. In both human and animal studies, acute and chronic ethanol exposure alters glutamate transmission
in the BLA and MDT. However, differences in subcellular localization and expression of CB1 receptors may
suggest that each of these excitatory inputs have different functions at PFC PV-INs from male and female
mice. In Aim 1, I will determine whether mGlu5 receptors regulate excitatory transmission (1.1) and
endocannabinoid plasticity (1.2) at BLA and MDT synapses on PFC PV-INs in a sex-specific manner. In Aim 2,
I will determine whether chronic drinking sex-dependently alters BLA and MDT synaptic strength (2.1) and
mGlu5 receptor signaling on PFC PV-INs (2.2). Preliminary data indicate female (but not male) mice with a
genetic deletion of mGlu5 from PV+ cells drink less when provided IA ethanol. In Aim 3, I will determine
whether PFC PV-INs mediate binge-drinking in PV-mGlu5-/- mice. The results of these experiments will improve
our understanding of the molecular components underlying ethanol-induced adaptations in synaptic plasticity
at specific PFC inputs and may direct therapeutic interventions for the treatment of AUD. By completing this
proposal, I will h...

## Key facts

- **NIH application ID:** 10994227
- **Project number:** 1F31AA031397-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Carly B Fabian
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994227

## Citation

> US National Institutes of Health, RePORTER application 10994227, Input specific adaptations to glutamatergic strength and plasticity on PFC PV-INs following ethanol drinking (1F31AA031397-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10994227. Licensed CC0.

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