# ZEBRAFISH MODELS FOR DRAVET SYNDROME RESEARCH AND DISCOVERY

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $510,261

## Abstract

Project Summary/Abstract
Dravet syndrome (DS), a catastrophic childhood epilepsy, is associated with severe intellectual disability,
impaired social development, persistent drug-resistant seizures and a high risk of sudden unexpected death in
epilepsy. Our recent investigation of zebrafish mutants featuring a loss-of-function sodium channel (scn1a)
mutation (e.g., a gene mutation identified in ~80% of DS patients) focused on drug discovery and
development, metabolic dysfunction and behavioral comorbidities. Using a high-throughput phenotype-based
screening strategy and medicinal chemistry, we screened nearly 3000 drugs, successfully identified a
serotonin (5HT) receptor mechanism underlying anti-seizure activity of clemizole and developed three novel
clemizole analogs. Using CRISPR/Cas9 genome editing technology we generated new zebrafish mutant lines
for chd2, gabrb3, pcdh19 and stxbp1 (e.g., de novo mutations seen in ~20% of DS patients). Interestingly,
stxbp1 and gabrb3 mutants exhibit epileptic phenotypes. We also designed and manufactured a microfluidic,
multi-channel electrode-integrated platform for long-term non-invasive electrophysiology on larval zebrafish
(Hong et al. 2016) and developed a calcium imaging-analysis pipeline for studying seizure macro- and micro-
networks in vivo (Liu and Baraban 2019). The proposed work will leverage these unique tools. Three specific
aims are proposed: (i) to resolve neural networks responsible for seizures in larval DS zebrafish, (ii) to perform
high-throughput drug screening using zebrafish and (iii) to further evaluate clemizole and related anti-seizure
compounds. Techniques will include automated locomotion tracking, in vivo zebrafish electrophysiology,
pharmacology, and fast calcium imaging using genetically encoded calcium- and voltage-sensitive indicators.
Our results promise to simultaneously advance our long-term goals (i) to better understand the
pathophysiology of genetic epilepsies and (ii) identify promising new treatment options for these intractable
conditions.

## Key facts

- **NIH application ID:** 10084931
- **Project number:** 5R01NS096976-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Scott C Baraban
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $510,261
- **Award type:** 5
- **Project period:** 2016-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084931

## Citation

> US National Institutes of Health, RePORTER application 10084931, ZEBRAFISH MODELS FOR DRAVET SYNDROME RESEARCH AND DISCOVERY (5R01NS096976-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10084931. Licensed CC0.

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