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Tucker Edmister S, Ibrahim R, Kakodkar R, et al. A zebrafish model for calcineurin-dependent brain function. Behav Brain Res. 2021;416:113544doi: 10.1016/j.bbr.2021.113544.
Tucker Edmister, S., Ibrahim, R., Kakodkar, R., Kreiling, J. A., & Creton, R. (2022). A zebrafish model for calcineurin-dependent brain function. Behavioural brain research, 416113544. https://doi.org/10.1016/j.bbr.2021.113544
Tucker Edmister, Sara, et al. "A zebrafish model for calcineurin-dependent brain function." Behavioural brain research vol. 416 (2022): 113544. doi: https://doi.org/10.1016/j.bbr.2021.113544
Tucker Edmister S, Ibrahim R, Kakodkar R, Kreiling JA, Creton R. A zebrafish model for calcineurin-dependent brain function. Behav Brain Res. 2022 Jan 07;416:113544. doi: 10.1016/j.bbr.2021.113544. Epub 2021 Aug 20. PMID: 34425181.
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Behav Brain Res. 2022 Jan 07;416:113544. doi: 10.1016/j.bbr.2021.113544. Epub 2021 Aug 20.

A zebrafish model for calcineurin-dependent brain function.

Behavioural brain research

Sara Tucker Edmister, Rahma Ibrahim, Rohit Kakodkar, Jill A Kreiling, Robbert Creton

Affiliations

  1. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
  2. Center for Computation and Visualization, Brown University, Providence, RI 02912, USA.
  3. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA. Electronic address: [email protected].

PMID: 34425181 DOI: 10.1016/j.bbr.2021.113544

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.

Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

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

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