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.

神经钙蛋白信号转导的小分子调节剂已被提议作为唐氏综合症和阿尔茨海默氏病的潜在疗法。模型预测，在唐氏综合症中，抑制的神经钙蛋白-NFAT 信号可能会被 proINDY 减轻，它激活 NFAT，激活 T 细胞的核因子。相反，钙调神经磷酸酶抑制剂环孢菌素和他克莫司可能会抑制阿尔茨海默病中升高的钙调神经磷酸酶信号传导。这种小分子治疗可能既有益又有害。目前的研究使用斑马鱼幼虫作为模型系统，检查了 proINDY、环孢菌素和他克莫司对行为的影响。为了抑制钙调磷酸酶信号，用环孢素和他克莫司处理幼虫。我们发现这些钙调神经磷酸酶抑制剂会诱发多动症，抑制视觉引导行为，声学过度兴奋和对声学刺激的习惯性降低。为了激活钙调神经磷酸酶-NFAT 信号，用 proINDY 处理幼虫。ProINDY 治疗降低了活动并刺激了视觉引导的行为，这与钙调神经磷酸酶抑制剂引起的行为变化相反。相反的影响表明活动和视觉引导行为受神经钙蛋白-NFAT 信号通路的调节。钙调神经磷酸酶抑制剂和 proINDY 的共同治疗进一步支持了钙调神经磷酸酶-NFAT 信号传导的核心作用，这对活动和视觉引导行为具有治疗作用。然而，这些共同治疗不利地增加了兴奋性，表明某些行为受其他钙调神经磷酸酶信号通路的调节。总体，