ArticleProceedings of the National Academy of Sciences of the United States of America2020
TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in zebrafish model of Tuberous Sclerosis Complex.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 38 citations in OpenAlex.
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- Animal models of autism spectrum disorder: Insights into genetic, structural and environmental models.Veterinarni medicina · 2025Review
- Hyperactive mTORC1 disrupts habenula function and light preference in zebrafish model of Tuberous sclerosis complex.iScience · 2024Article
- Psilocybin induces acute anxiety and changes in amygdalar phosphopeptides independently from the 5-HT2A receptor.iScience · 2024Article
- Vitamin D in tuberous sclerosis complex-associated tumors.Frontiers in pediatrics · 2024Article
- Induction of seizures and initiation of epileptogenesis by pilocarpine in zebrafish larvae.Frontiers in molecular neuroscience · 2024Article
- Diving into the zebrafish brain: exploring neuroscience frontiers with genetic tools, imaging techniques, and behavioral insights.Frontiers in molecular neuroscience · 2024Review
- Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Zebrafish as a Model Organism for Studying Pathologic Mechanisms of Neurodegenerative Diseases and other Neural Disorders.Cellular and molecular neurobiology · 2023Review
- Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy.Brain : a journal of neurology · 2023Review
- Developing Novel Experimental Models of m-TORopathic Epilepsy and Related Neuropathologies: Translational Insights from Zebrafish.International journal of molecular sciences · 2023Review
- Leukocyte invasion of the brain after peripheral trauma in zebrafish (Danio rerio).Experimental & molecular medicine · 2022Article
- Hyperactivation of mTORC1 in a double hit mutant zebrafish model of tuberous sclerosis complex causes increased seizure susceptibility and neurodevelopmental abnormalities.Frontiers in cell and developmental biology · 2022Article
- Teleost Fish and Organoids: Alternative Windows Into the Development of Healthy and Diseased Brains.Frontiers in molecular neuroscience · 2022Review
- Phenotypic analysis of catastrophic childhood epilepsy genes.Communications biology · 2021Article
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- Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?Molecular neurobiology · 2021Article
- Knockout ofInternational journal of molecular sciences · 2020Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tuberous Sclerosis Complex (TSC) is a rare genetic disease that manifests with early symptoms, including cortical malformations, childhood epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Cortical malformations arise during embryonic development and have been linked to childhood epilepsy before, but the underlying mechanisms of this relationship remain insufficiently understood. Zebrafish have emerged as a convenient model to study elementary neurodevelopment; however, without in-depth functional analysis, the Tsc2-deficient zebrafish line cannot be used for studies of TANDs or new drug screening. In this study, we found that the lack of Tsc2 in zebrafish resulted in heterotopias and hyperactivation of the mTorC1 pathway in pallial regions, which are homologous to the mammalian cortex. We observed commissural thinning that was responsible for brain dysconnectivity, recapitulating TSC pathology in human patients. The lack of Tsc2 also delayed axonal development and caused aberrant tract fasciculation, corresponding to the abnormal expression of genes involved in axon navigation. The mutants underwent epileptogenesis that resulted in nonmotor seizures and exhibited increased anxiety-like behavior. We further mapped discrete parameters of locomotor activity to epilepsy-like and anxiety-like behaviors, which were rescued by reducing tyrosine receptor kinase B (TrkB) signaling. Moreover, in contrast to treatment with vigabatrin and rapamycin, TrkB inhibition rescued brain dysconnectivity and anxiety-like behavior. These data reveal that commissural thinning results in the aberrant regulation of anxiety, providing a mechanistic link between brain anatomy and human TANDs. Our findings also implicate TrkB signaling in the complex pathology of TSC and reveal a therapeutic target.
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