TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in zebrafish model of Tuberous Sclerosis Complex

Kedra, M., Banasiak, K., Kisielewska, K., Wolinska-Niziol, L., Jaworski, J., Zmorzynska, J.
Proceedings of the National Academy of Sciences of the United States of America   117(4): 2170-2179 (Journal)
Registered Authors
TANDs, TrkB, Tuberous Sclerosis Complex, anxiety, brain dysconnectivity
MeSH Terms
  • Animals
  • Anxiety/genetics
  • Anxiety/metabolism*
  • Anxiety/psychology
  • Disease Models, Animal
  • Epilepsy/genetics
  • Epilepsy/metabolism*
  • Epilepsy/psychology
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics
  • Intracellular Signaling Peptides and Proteins/metabolism*
  • Mechanistic Target of Rapamycin Complex 1/genetics
  • Mechanistic Target of Rapamycin Complex 1/metabolism
  • Seizures/genetics
  • Seizures/metabolism
  • Seizures/psychology
  • Tuberous Sclerosis/genetics
  • Tuberous Sclerosis/metabolism*
  • Tuberous Sclerosis/psychology
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
31932427 Full text @ Proc. Natl. Acad. Sci. USA
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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes