A zebrafish model for calcineurin-dependent brain function.
A zebrafish model for calcineurin-dependent brain function.
复制标题
DOI：
10.1016/j.bbr.2021.113544
复制
发表时间：
2022-01-07
影响因子：
2.7
通讯作者：
Creton R
中科院分区：
文献类型：
--
作者：
Tucker Edmister S;Ibrahim R;Kakodkar R;Kreiling JA;Creton R
钙调神经磷酸酶信号转导的小分子调节剂已被提出作为唐氏综合征和阿尔茨海默病的潜在治疗剂。模型预测，在唐氏综合征中，抑制的钙调神经磷酸酶-NFAT信号传导可以通过proINDY来减轻，proINDY激活NFAT，活化T细胞的核因子。相反，阿尔茨海默病中升高的钙调神经磷酸酶信号传导可以用钙调神经磷酸酶抑制剂环孢霉素和他克莫司抑制。这种小分子治疗可能具有有益和不利的影响。目前的研究探讨了proINDY，环孢素和他克莫司对行为的影响，使用斑马鱼幼虫作为模型系统。为了抑制钙调磷酸酶信号传导，用环孢霉素和他克莫司处理幼虫。我们发现，这些钙调磷酸酶抑制剂诱导多动，抑制视觉引导的行为，听觉过度兴奋和减少习惯性的声音刺激。为了激活钙调神经磷酸酶-NFAT信号传导，用proINDY处理幼虫。ProINDY治疗减少活动并刺激视觉引导行为，与钙调磷酸酶抑制剂诱导的行为变化相反。相反的效果表明，活动和视觉引导的行为是由钙调神经磷酸酶-NFAT信号通路。钙调神经磷酸酶-NFAT信号传导的中心作用进一步得到钙调神经磷酸酶抑制剂和proINDY的共同治疗的支持，其对活动和视觉引导行为具有治疗效果。然而，这些共同处理不利地增加了兴奋性，这表明一些行为是由其他钙调神经磷酸酶信号通路调节的。总的来说，开发的方法提供了一个有效的高通量平台，用于评估钙调磷酸酶信号传导的调节剂，在复杂的神经系统中恢复神经功能，同时避免不良副作用。
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.
登录
查看更多内容
DOI：
10.9758/cpn.2017.15.1.1
发表时间：
2017-02-28
期刊：
Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology
影响因子：
--
作者：
Kocahan S;Doğan Z
通讯作者：
Doğan Z
影响因子：
4
作者：
Liew WC;Orbán L
通讯作者：
Orbán L
影响因子：
14.8
作者：
Bruni G;Rennekamp AJ;Velenich A;McCarroll M;Gendelev L;Fertsch E;Taylor J;Lakhani P;Lensen D;Evron T;Lorello PJ;Huang XP;Kolczewski S;Carey G;Caldarone BJ;Prinssen E;Roth BL;Keiser MJ;Peterson RT;Kokel D
通讯作者：
Kokel D
影响因子：
64.8
作者：
Arron, Joseph R.;Winslow, Monte M.;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
6
作者：
Castro, Paula;Zaman, Shahid;Holland, Anthony
通讯作者：
Holland, Anthony