# Generating mouse models with cell type-specific and reversible GABA deficiency

> **NIH NIH R21** · UNIVERSITY OF CHICAGO · 2024 · $196,296

## Abstract

ABSTRACT
 GABAergic neurons are the main inhibitory neurons in the adult nervous system. There are diverse cortical
and subcortical GABAergic interneurons and projection neurons with different physiological properties,
connectivity, and functions. However, few studies have been able to investigate the functions of specific
subclasses by perturbing GABA release selectively. We propose an approach to target GABA synthesis in
subclasses of GABAergic neurons. GAD activity requires the cofactor pyridoxal-5-phosphate (PLP). PLP
deficiency can be achieved by knocking out the rate limiting enzyme in PLP synthesis: pyridoxine-5-phosphate
oxidase (PNPO). Moreover, PLP deficiency can be rescued by systemic PLP administration. We therefore
propose to generate cell type specific PNPO deficiency mouse models. We will first generate models with
GABA deficiency in well-studied but highly distinct cell types to test the feasibility of our approach: 1) the
parvalbumin (PV)-positive GABAergic neurons; 2) the VIP-positive GABAergic neurons; 3) the striatal
dopamine D1 receptor expressing neurons; and 4) the striatal dopamine D2 receptor expressing neurons. Mice
will be assessed for general health, feeding, drinking, sleep, and potential seizures. In addition, working
memory, reference memory, reversal learning, motor coordination and motor learning will be examined. Brain
morphology and electrophysiology will be assessed. Levels of GABA, other PNPO-dependent
neurotransmitters, and their metabolites will be measured. The main goal of this R21 application is to test the
feasibility of such an approach. These models are potentially significant research tools for the research
community and may have a broad impact given the diverse distribution and functions of different GABAergic
projection neurons and interneurons.

## Key facts

- **NIH application ID:** 10843182
- **Project number:** 5R21NS132597-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Xiaoxi Zhuang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $196,296
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843182

## Citation

> US National Institutes of Health, RePORTER application 10843182, Generating mouse models with cell type-specific and reversible GABA deficiency (5R21NS132597-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10843182. Licensed CC0.

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