# Probing GABAa receptor function and plasticity with light

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $432,918

## Abstract

GABA and glutamate are the main inhibitory and excitatory neurotransmitters in the brain.
Activity-dependent redistribution of glutamate receptors contributes to excitatory long-term
synaptic plasticity, learning and memory. A similar redistribution of GABAA receptors
(GABAARs) has been shown to occur in neuronal culture, but the functional significance of this
process in intact brain circuits remains unclear. Our goal is to better understand the role that
GABAA receptors play in synaptic plasticity in the hippocampus, a brain region crucial for
learning and memory. We have developed photoswitch chemicals that allow light to reversibly
block GABAA receptors with high spatial and temporal precision and absolute specificity for a
specified mutant α-subunit. Here we focus on receptors containing either the broadly-
expressed α1-subunit, or the hippocampus-enriched α5-subunit. To enable photo-control of
endogenous receptors, we have developed knock-in mice with photoswitch-ready version of α1
or α5 replacing their wild-type counterparts. Using these mice and novel intrabody probes that
light-up or disrupt GABAARs scaffolds, we will evaluate where α1- and α5-GABAARs are in
neurons, how they contribute to synaptic function, and what role they play in synaptic
plasticity. Aim 1 is to map the distribution of the two GABAA types in hippocampal neurons.
This includes determining whether they are expressed in proximal to distal dendritic gradients,
determining whether they are aggregated at synapses or dispersed extrasynapatically, and
determining their individual contributions to inhibitory synaptic transmission from different
identified inhibitory interneurons. Aim 2 is to investigate how neuronal activity alters the
distribution of GABAARs. This includes using the photoswitch as a stable tag to evaluate
whether activity alters the lifespan and lateral mobility of the receptors on the plasma
membrane. Aim 3 is to investigate how GABAARs alter excitatory long-term synaptic
plasticity. This includes investigating the impact of the GABAARs on induction of long-term
potentiation and depression and NMDA receptor signaling. The knowledge gained from this
work will fill a gaping hole in our understanding of brain function and may reveal new
treatment strategies for memory disorders and other neurological diseases.
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## Key facts

- **NIH application ID:** 9935132
- **Project number:** 5R01NS100911-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** RICHARD H KRAMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,918
- **Award type:** 5
- **Project period:** 2017-04-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935132

## Citation

> US National Institutes of Health, RePORTER application 9935132, Probing GABAa receptor function and plasticity with light (5R01NS100911-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9935132. Licensed CC0.

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