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Updated: Jan 8, 2026
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Behavioral And Physiological Analysis In A Zebrafish Model Of Epilepsy
Published on: October 19, 2021
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Early death and neuronal abnormalities in depdc5 loss-of-function mosaic zebrafish models
Sneham Tiwari1,2, Christopher M LaCoursiere1, Hyun Yong Koh1,3,4
1Epilepsy Genetics Program and Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Boston, MA.
Biorxiv : the Preprint Server for Biology
|December 22, 2025
Summary
Mosaic DEPDC5 variants cause epilepsy and early death. Zebrafish models with DEPDC5 loss-of-function mutations show seizure-like behaviors and increased apoptosis, providing a relevant model for studying these conditions.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- DEPDC5 (DEP domain-containing protein 5) is a repressor of the mTORC1 signaling pathway.
- Genetic variants in DEPDC5 are linked to focal epilepsies, including those with mosaic variants and focal cortical dysplasia.
- Somatic mosaic variants in DEPDC5 are implicated in brain malformations.
Purpose of the Study:
- To investigate the role of DEPDC5 in human epilepsy associated with mosaic variants.
- To generate and characterize mosaic loss-of-function zebrafish models for DEPDC5.
- To explore the relationship between DEPDC5 mutational load and epilepsy phenotypes.
Main Methods:
- Generation of mosaic depdc5 loss-of-function zebrafish using homology-based constructs and tdTomato labeling.
- Assessment of larval survival, body/head size, and swimming behavior in mosaic zebrafish.
- Analysis of seizure-like behavior, neuronal hyperexcitability via local field potential recordings, and apoptosis using acridine orange staining.
Main Results:
- Mosaic depdc5 zebrafish exhibited early larval death (~50% by 7 dpf) and reduced body/head size.
- Significant reductions in swimming distance and velocity were observed in mosaic depdc5 zebrafish.
- Higher mutational load (depdc5++) correlated with increased posture loss episodes (seizure-like behavior) and neuronal hyperexcitability.
- Early apoptosis was detected in mosaic depdc5 zebrafish compared to controls.
Conclusions:
- Mosaic depdc5 zebrafish models accurately recapitulate key features of human DEPDC5-related epilepsy, including early death and seizure activity.
- These zebrafish models offer a clinically relevant platform for studying the pathogenesis of mosaic DEPDC5-related epilepsy.
- The findings highlight the critical role of DEPDC5 in neuronal development and function, with loss-of-function contributing to epilepsy and lethality.
