# B3 subunit phosphorylation determines synaptic and extrasynaptic GABAAR assembly

> **NIH NIH F31** · TUFTS UNIVERSITY BOSTON · 2022 · $13,568

## Abstract

Project Summary/Abstract
Impaired inhibitory signaling via γ-aminobutyric acid type A receptors (GABAARs) underlies the pathophysiology
of several neuropsychiatric disorders including autism spectrum disorder. Neuronal inhibition is regulated by α1-
containing synaptic GABAARs and α4-containing extrasynaptic GABAARs that mediate phasic and tonic
inhibition, respectively. Both subtypes are required for proper control of inhibitory neurotransmission, yet the
mechanism by which neurons control the assembly of these two subtypes has not been elucidated. In addition,
while the β3 subunits, which are shared by both α1- and α4-containing GABAAR subtypes, regulate the surface
expression of GABAARs via phosphorylation of the serine 408 and serine 409 residues (S408/9), the role of
S408/9 in mediating GABAAR assembly remains to be discovered.
This proposal combines biochemical and molecular biology approaches to test the novel hypothesis that
phospho-regulation of S408/9 regulates the assembly of α1-containing synaptic and α4-containing
extrasynaptic GABAAR subtypes, and that mutating S408/9 compromises GABAAR assembly and thus
GABAergic inhibition. Examining the subunit compositions, proteomes, and levels of phosphorylated S408/9
of α1- and α4-containing GABAARs in adult C57Bl/6 mouse brains will unveil the structural properties and
mechanisms underlying the assembly of endogenous α1- and α4-containing GABAARs (Aim 1). Investigating
how the alanine substitutions at S408/9 (S408/9A) alter the subunit compositions, proteomes, sub-cellular
localizations, and half-lives of α1- and α4-containing GABAARs in S408/9A animals will provide information on
the role of S408/9 in the assembly of GABAAR subtypes (Aim 2). Collectively, these aims will discover the
mechanisms involved in the sorting of α1 and α4 subunits into the two GABAAR subtypes that mediate phasic
and tonic inhibition. The long-term objective of this project is to identify S408/9 as novel therapeutic targets for
disease conditions with impaired GABAergic inhibition.
For successful completion of this project, the applicant will be thoroughly trained in biochemical, molecular
biology, and imaging techniques, as well as in bioinformatics. In addition, the applicant will be provided with
numerous opportunities for training in science communication, mentorship, and career exploration. The Moss
laboratory at Tufts University fosters an environment where the applicant will be intellectually engaged and
supported with all necessary facility, equipment, and guidance to ensure productive graduate training, and to
prepare the applicant for a flourishing career as an independent research scientist in translational neuroscience.

## Key facts

- **NIH application ID:** 10425290
- **Project number:** 5F31MH126542-02
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Catherine Choi
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $13,568
- **Award type:** 5
- **Project period:** 2021-06-01 → 2022-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425290

## Citation

> US National Institutes of Health, RePORTER application 10425290, B3 subunit phosphorylation determines synaptic and extrasynaptic GABAAR assembly (5F31MH126542-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10425290. Licensed CC0.

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