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Peer-reviewedCC BYInternational journal of medical sciences

The deficiency of htr6 gene results in aberrant brain development and epileptiform discharges in zebrafish larvae.

  • Hongyuan Chu1,2,3
  • Hao Wang1,2,3
  • Sijia Wen1,2,3
  • Renqiuguo Li1,2,3
  • Junjiao Zhang1,2,3
  • Fan Zhang1,2,3
  • Huaxia Luo1,2,3
  • Ye Wu1,2,3
  • Jingmin Wang1,2,3,4
  • Kai Gao1,2,3,4
  • Yuwu Jiang1,2,3,4,5
5 affiliations
  1. 1Children's Medical Center, Peking University First Hospital, Beijing, China.
  2. 2Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, China.
  3. 3Children Epilepsy Center, Peking University First Hospital, Beijing, China.
  4. 4Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, China.
  5. 5Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, China.
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Abstract

Background

The 5-Hydroxytryptamine Receptor 6 (HTR6) is a G protein-coupled receptor implicated in neurodevelopmental disorders and epilepsy. Our previous studies identified a somatic HTR6 mutation in brain surgical specimens from patients with focal cortical dysplasia type II, suggesting its potential involvement in disease pathogenesis.Objective

To investigate the functional role of the htr6 in zebrafish, focusing on its impact on neurodevelopment and seizure susceptibility.Methods

A F0 mosaic htr6 crispant zebrafish model was generated using CRISPR/Cas9 and validated by sequencing and TIDE analysis. Morphological and central nervous system (CNS) abnormalities were assessed at 5 days post-fertilization (dpf) by bright-field and Tg (HuC: eGFP) fluorescence imaging. Survival was monitored to 21 dpf. Locomotor behavior was evaluated using DanioVision, and epileptiform activity was examined by local field potential recording. Human HTR6 mRNA rescue experiments, transcriptome sequencing, and qPCR validation were also performed.Results

Deficiency of htr6 resulted in significant reductions in interocular and central nervous system areas. In addition, F0 mosaic htr6 crispant showed significantly reduced survival compared with Cas9 controls. While locomotor activity was markedly unaffected, electrophysiological recordings revealed epileptiform events in 9 of 24 F0 mosaic htr6 crispant but none in the Cas9 controls. Co-injection of human HTR6 mRNA rescued both neurodevelopmental abnormalities and epileptiform activity. Transcriptome analysis identified 402 differentially expressed genes, including the upregulation of 355 and the downregulation of 47 genes, suggesting profound neuronal impacts from htr6 deficiency. KEGG pathway enrichment analysis linked these changes to ABC transporters and metabolic pathways, demonstrating the significance of htr6 in maintaining neuronal health.Conclusion

Deficiency of htr6 in zebrafish results in abnormal brain development and epileptiform activity, underscoring its critical role in neurodevelopment and neuronal excitability. These findings suggest the importance of HTR6 in neurodevelopment and epilepsy, providing a foundation for further research on therapeutic strategies targeting HTR6-related pathways in neurological disorders.

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Cite

BibTeXRIS
BibTeX
@article{chu2026deficiency,
  title = {{The deficiency of htr6 gene results in aberrant brain development and epileptiform discharges in zebrafish larvae.}},
  author = {Hongyuan Chu and Hao Wang and Sijia Wen and Renqiuguo Li and Junjiao Zhang and Fan Zhang and Huaxia Luo and Ye Wu and Jingmin Wang and Kai Gao and Yuwu Jiang},
  journal = {International journal of medical sciences},
  year = {2026},
  month = oct,
  doi = {10.7150/ijms.135746},
  url = {https://europepmc.org/article/MED/42910141},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - The deficiency of htr6 gene results in aberrant brain development and epileptiform discharges in zebrafish larvae.
AU  - Hongyuan Chu
AU  - Hao Wang
AU  - Sijia Wen
AU  - Renqiuguo Li
AU  - Junjiao Zhang
AU  - Fan Zhang
AU  - Huaxia Luo
AU  - Ye Wu
AU  - Jingmin Wang
AU  - Kai Gao
AU  - Yuwu Jiang
PY  - 2026
DA  - 2026/10/02
JO  - International journal of medical sciences
DO  - 10.7150/ijms.135746
UR  - https://europepmc.org/article/MED/42910141
AB  - Background  The 5-Hydroxytryptamine Receptor 6 (HTR6) is a G protein-coupled receptor implicated in neurodevelopmental disorders and epilepsy. Our previous studies identified a somatic HTR6 mutation in brain surgical specimens from patients with focal cortical dysplasia type II, suggesting its potential involvement in disease pathogenesis.Objective  To investigate the functional role of the htr6 in zebrafish, focusing on its impact on neurodevelopment and seizure susceptibility.Methods  A F0 mosaic htr6 crispant zebrafish model was generated using CRISPR/Cas9 and validated by sequencing and TIDE analysis. Morphological and central nervous system (CNS) abnormalities were assessed at 5 days post-fertilization (dpf) by bright-field and Tg (HuC: eGFP) fluorescence imaging. Survival was monitored to 21 dpf. Locomotor behavior was evaluated using DanioVision, and epileptiform activity was examined by local field potential recording. Human HTR6 mRNA rescue experiments, transcriptome sequencing, and qPCR validation were also performed.Results  Deficiency of htr6 resulted in significant reductions in interocular and central nervous system areas. In addition, F0 mosaic htr6 crispant showed significantly reduced survival compared with Cas9 controls. While locomotor activity was markedly unaffected, electrophysiological recordings revealed epileptiform events in 9 of 24 F0 mosaic htr6 crispant but none in the Cas9 controls. Co-injection of human HTR6 mRNA rescued both neurodevelopmental abnormalities and epileptiform activity. Transcriptome analysis identified 402 differentially expressed genes, including the upregulation of 355 and the downregulation of 47 genes, suggesting profound neuronal impacts from htr6 deficiency. KEGG pathway enrichment analysis linked these changes to ABC transporters and metabolic pathways, demonstrating the significance of htr6 in maintaining neuronal health.Conclusion  Deficiency of htr6 in zebrafish results in abnormal brain development and epileptiform activity, underscoring its critical role in neurodevelopment and neuronal excitability. These findings suggest the importance of HTR6 in neurodevelopment and epilepsy, providing a foundation for further research on therapeutic strategies targeting HTR6-related pathways in neurological disorders.
SN  - 1449-1907
ER  -