PUBLICATION
A zebrafish model for calcineurin-dependent brain function
- Authors
- Edmister, S.T., Ibrahim, R., Kakodkar, R., Kreiling, J.A., Creton, R.
- ID
- ZDB-PUB-210824-17
- Date
- 2021
- Source
- Behavioural brain research 416: 113544 (Journal)
- Registered Authors
- Creton, Robbert
- Keywords
- Alzheimer’s disease, Calcineurin signaling, Down syndrome, Zebrafish, behavior
- MeSH Terms
-
- Animals
- Brain/metabolism*
- Calcineurin/pharmacology*
- Calcineurin Inhibitors/pharmacology*
- Cyclosporine/antagonists & inhibitors
- Cyclosporine/pharmacology*
- Hyperkinesis/chemically induced
- NFATC Transcription Factors/metabolism
- Signal Transduction/drug effects*
- Zebrafish/metabolism*
- PubMed
- 34425181 Full text @ Behav. Brain Res.
Citation
Edmister, S.T., Ibrahim, R., Kakodkar, R., Kreiling, J.A., Creton, R. (2021) A zebrafish model for calcineurin-dependent brain function. Behavioural brain research. 416:113544.
Abstract
Small-molecule modulators of calcineurin signaling have been proposed as potential therapeutics in Down syndrome and Alzheimer's disease. Models predict that in Down syndrome, suppressed calcineurin-NFAT signaling may be mitigated by proINDY, which activates NFAT, the nuclear factor of activated T-cells. Conversely, elevated calcineurin signaling in Alzheimer's disease may be suppressed with the calcineurin inhibitors cyclosporine and tacrolimus. Such small-molecule treatments may have both beneficial and adverse effects. The current study examines the effects of proINDY, cyclosporine and tacrolimus on behavior, using zebrafish larvae as a model system. To suppress calcineurin signaling, larvae were treated with cyclosporine and tacrolimus. We found that these calcineurin inhibitors induced hyperactivity, suppressed visually-guided behaviors, acoustic hyperexcitability and reduced habituation to acoustic stimuli. To activate calcineurin-NFAT signaling, larvae were treated with proINDY. ProINDY treatment reduced activity and stimulated visually-guided behaviors, opposite to the behavioral changes induced by calcineurin inhibitors. The opposing effects suggest that activity and visually-guided behaviors are regulated by the calcineurin-NFAT signaling pathway. A central role of calcineurin-NFAT signaling is further supported by co-treatments of calcineurin inhibitors and proINDY, which had therapeutic effects on activity and visually-guided behaviors. However, these co-treatments adversely increased excitability, suggesting that some behaviors are regulated by other calcineurin signaling pathways. Overall, the developed methodologies provide an efficient high-throughput platform for the evaluation of modulators of calcineurin signaling that restore neural function, while avoiding adverse side effects, in a complex neural system.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping