A zebrafish model for calcineurin-dependent brain function

Behav Brain Res. 2022 Jan 7:416:113544. doi: 10.1016/j.bbr.2021.113544. Epub 2021 Aug 20.


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.

Keywords: Alzheimer’s disease; Behavior; Calcineurin signaling; Down syndrome; Zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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*


  • Calcineurin Inhibitors
  • NFATC Transcription Factors
  • Cyclosporine
  • Calcineurin