# Synaptic Dysfunction of Neural Circuits in Neurodevelopmental Disorders

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $346,719

## Abstract

PROJECT SUMMARY/ABSTRACT
Ongoing systematic human genetic studies of neurodevelopmental disorders continue to uncover pathogenic
mutations in genes encoding synaptic proteins, demonstrating the importance of these proteins for neurological
and neuropsychiatric functions. Although the molecular and cellular functions of many such synaptic proteins
have been studied to various extents, the functional roles of these proteins in neural circuits and behaviors are
poorly understood because in-depth neurological and behavioral studies in animal models are often lacking.
Consequently, the pathological mechanisms underlying these synaptic disorders remain elusive. This
knowledge gap can be significantly narrowed by studying a few prioritized genes that are highly penetrant and
affect a broad spectrum of neurological and neuropsychiatric features common among neurodevelopmental
disorders. The gene encoding syntaxin-binding protein 1 is one such exciting example because it is one of a
few genes most frequently mutated in neurodevelopmental disorders. The absence of syntaxin-binding protein
1 abolishes neurotransmitter release. This essential function is well understood at the molecular level, yet it
remains unknown how its haploinsufficiency in humans causes a range of neurological impairments including
epileptic seizures and intellectual disabilities. Thus, the overall goal of this project is to decipher the synaptic
dysfunction of neural circuits in the mouse models of this disorder and understand their relevance to disease
pathogenesis at the whole-organism level. The apparently paradoxical effects of syntaxin-binding protein 1
deletion and haploinsufficiency lead to the central hypothesis that its haploinsufficiency preferentially impairs
GABAergic inhibitory transmitter release and causes an imbalance between excitation and inhibition, resulting
in hyperexcitable neural circuits and neurological deficits, which can be reversed upon restoring protein
function in adulthood. We propose to combine genetic manipulations with optogenetic, physiological, and
behavioral methods to delineate synapse-specific alterations of neurotransmission in cortical circuits (Aim 1), to
determine the contributions of specific cell types to the pathogenesis of the disorder (Aims 2 and 3), and to test
the reversibility of the disease phenotypes in adulthood (Aim 3). This project shifts the research focus of
syntaxin-binding protein 1 from neurotransmitter release per se to its function at the levels of neural circuitry
and behavior. The proposed research will provide mechanistic insights into the pathogenesis of this
devastating neurodevelopmental disorder. Beyond this particular disorder, understanding how disruption of
excitation-inhibition balance affects neural circuits and behaviors will have ramifications for a growing list of
neurodevelopmental disorders caused by mutations that alter synaptic transmission.

## Key facts

- **NIH application ID:** 10101700
- **Project number:** 5R01NS100893-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Mingshan Xue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,719
- **Award type:** 5
- **Project period:** 2017-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101700

## Citation

> US National Institutes of Health, RePORTER application 10101700, Synaptic Dysfunction of Neural Circuits in Neurodevelopmental Disorders (5R01NS100893-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10101700. Licensed CC0.

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