# Cellular and Molecular Mechanisms of Behavioral Dysfunction in a Zebrafish Model of CHARGE Syndrome

> **NIH NIH R21** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2021 · $411,240

## Abstract

Project Summary
CHARGE syndrome is a rare, multi-system disorder that affects approximately 1 in 10,000 live births. The most
common symptoms include ocular coloboma, choanal atresia, heart defects, genital abnormalities, ear
malformations, and an array of neuro-behavioral difficulties. Sensory under- or over-load, motor impairments,
enhanced pain, sleep disorders, attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder
(OCD), intellectual disability, anxiety, and autism are all frequently observed in CHARGE. Treatments for these
behavioral symptoms are limited, highlighting an area of critical need in understanding the mechanisms
underlying these defects in order to develop new therapeutic approaches. Two-thirds of CHARGE cases are
caused by loss-of-function mutations in chd7, which encodes a DNA-binding, ATP-dependent chromatin
remodeling protein. chd7 is highly expressed in the developing vertebrate brain and regulates transcription of
several key neurodevelopmental genes, but direct cellular and molecular links between chd7 function and
behavioral regulation have not been established. This project leverages the larval zebrafish model, which has
rapidly emerged as a powerful system for investigating the development and function of behavioral circuits as
well as human genetic disease. Using CRISPR/Cas9 we have established a chd7-null line and have
characterized several morphological and behavioral phenotypes reflective of CHARGE. In response to acoustic
stimuli, chd7 mutants perform normal short-latency startle responses (SLCs) but have impaired long-latency
escape responses (LLCs). Similarly, chd7 mutants respond normally to increases in illumination but are deficient
in responding to decreases in illumination. These deficits are independent of morphological defects in the eyes
and ears, indicating that chd7 likely regulates specific behavioral circuits in the brain. In Aim 1 we will
systematically interrogate the known circuit elements driving these behaviors using in vivo calcium imaging and
cell-specific rescue to locate the sites of chd7 action. We will then comprehensively define the brain regions that
are dependent on chd7 using whole-brain morphometry and activity analyses. In Aim 2 we will apply state-of-
the-art proteomic and transcriptomic approaches to identify molecular pathways that link chd7 with these
changes in brain structure and function. By analyzing samples from three developmental timepoints, we will also
define the temporal dynamics of these changes. Finally, we will use a systematic CRISPR/Cas9 approach to
validate the top proteomics- and transcriptomics-based chd7 targets in vivo by measuring brain development
and behavior in mutant larvae. Overall, the results of this work will establish direct links between chd7, its
molecular targets, and behavioral circuits. Furthermore, these aims will generate a powerful set of broadly useful
resources for interrogating the cellular and molecular bases of ch...

## Key facts

- **NIH application ID:** 10372659
- **Project number:** 1R21NS120079-01A1
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** Kurt C. Marsden
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $411,240
- **Award type:** 1
- **Project period:** 2021-09-10 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372659

## Citation

> US National Institutes of Health, RePORTER application 10372659, Cellular and Molecular Mechanisms of Behavioral Dysfunction in a Zebrafish Model of CHARGE Syndrome (1R21NS120079-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10372659. Licensed CC0.

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