# Revealing distinct mechanisms and functions of neuronal inhibition in vivo

> **NIH NIH F32** · YALE UNIVERSITY · 2021 · $74,886

## Abstract

Summary/Abstract
Communication between neurons within and across brain regions is essential for proper brain function. This
communication is mediated by neuronal excitability, which is tightly controlled by neuronal inhibition. GABAARs
play an essential role in mediating neuronal inhibition, and dysregulation in GABAAR activity has been
implicated in a variety of disorders, including autism, epilepsy and schizophrenia. GABAARs mediate inhibitory
synaptic transmission through two distinct mechanisms, phasic and tonic inhibition. While phasic inhibition is
fast and localized at synapses, tonic inhibition is persistent and spreads throughout the dendrite and the cell
body.
Despite the importance of phasic and tonic inhibition in controlling neuronal excitability, little is known about
their distinct roles in vivo. This is due to difficulty in eliminating one type of inhibition without affecting the other.
The subunit composition of the GABAARs that mediate phasic and tonic inhibition is highly redundant. GARLHs
are auxiliary subunits that control the synaptic localization of GABAARs, without affecting their surface
expression. In the present study, I aim to reveal the distinct roles of phasic and tonic inhibition in vivo by
making use of a cell-specific GARLH knockout mouse, where phasic inhibition has been abolished without
alterations in tonic inhibition. Furthermore, I have found that both phasic and tonic inhibition are abolished in a
novel conditional triple knockout mice of GABAAR β1/2/3. By contrasting the behavioral performance and the
cell biology of synapses between these two knockout mice, I will be able to discern the specific roles of phasic
and tonic inhibition in motor behavior and in the formation and stability of synaptic circuits.
Successful completion of this proposal will reveal critical roles for synaptic and extrasynaptic GABAARs in the
synaptic architecture of neurons, and motor behavior. It will also reveal novel molecules responsible for the
synaptic localization of GABAARs in the adult brain. Combined, these results will provide valuable insight in our
understanding of inhibitory neurotransmission in the brain, and help identify key therapeutic targets for motor
disorders.

## Key facts

- **NIH application ID:** 10188373
- **Project number:** 5F32AG060717-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Erika Hoyos-Ramirez
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $74,886
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188373

## Citation

> US National Institutes of Health, RePORTER application 10188373, Revealing distinct mechanisms and functions of neuronal inhibition in vivo (5F32AG060717-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10188373. Licensed CC0.

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