# Illuminating GABAergic Signaling in Neurodevelopmental Disorders

> **NIH NIH DP5** · BAYLOR COLLEGE OF MEDICINE · 2022 · $396,250

## Abstract

PROJECT SUMMARY
Technological advances have accelerated the discovery of genetic etiologies for many neurodevelopmental
disorders such as intellectual disability, autism spectrum disorder, and epilepsy. The emerging theme of
altered inhibitory -aminobutyric-acid-(GABA)-ergic signaling in many of these disorders suggest a common
pathogenic mechanism despite heterogeneous etiologies. Although comprising only ~20% of neurons in the
brain, GABAergic neurons are key for virtually all aspects of neurobiology, from neural development to network
dynamics, but there remains a knowledge gap regarding how genetic alterations perturb GABAergic signaling
and result in cognitive and behavioral changes. This gap needs to be addressed in order to bridge molecular
functions to disease mechanisms and expand our understanding of inhibitory neurobiology.
We, and others, recently found that heterozygous loss-of-function (LOF) gene variants affecting evolutionarily
conserved residues in EBF3 (Early B-cell Factor 3), a COE transcription factor, cause a neurodevelopmental
disorder called Hypotonia Ataxia and Delayed Development Syndrome (HADDS, MIM#617330). EBF3 and the
other mammalian COE factors are crucial for the development of inhibitory GABAergic neurons, but were not
previously associated with neurologic disorders. These findings suggest that COE transcription factors are a
novel group of genes in the pathogenesis of neurodevelopmental disorders.
The overall goal of this project is to decipher the transcriptional dysregulation of inhibitory signaling in fly and
mouse models of COE factor-related disorders and understand the relevance of these alterations to disease.
Known molecular and cellular functions of COE factors in inhibitory GABAergic neuronal development leads to
the hypothesis that altered COE transcription factor function perturb inhibitory signaling resulting in
neurological deficits. I will combine human genomics and genetic manipulations in fly and mouse models with
molecular, neurophysiological, and behavioral analyses to determine the role of COE factor dysfunction in
neurodevelopmental disorders (Aim 1), delineate disrupted inhibitory signaling in EBF3-related disorders (Aim
2), and elucidate the mechanisms of COE transcription factor regulation of GABAergic signaling (Aim 3).
This project shifts the research focus of COE transcription factors, and EBF3 in particular, from the molecular
and cellular levels to neural networks and behaviors. These studies have the potential to provide mechanistic
insights into the highly prevalent group of disorders distinguished by intellectual disability and autism.
Furthermore, the gain in understanding of how transcriptional dysregulation of inhibitory neurons affects neural
activity and behaviors will impact the growing list of disorders associated with abnormal inhibitory signaling.

## Key facts

- **NIH application ID:** 10487398
- **Project number:** 5DP5OD026428-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** HSIAO-TUAN CHAO
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2018-09-18 → 2025-08-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487398

## Citation

> US National Institutes of Health, RePORTER application 10487398, Illuminating GABAergic Signaling in Neurodevelopmental Disorders (5DP5OD026428-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10487398. Licensed CC0.

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