The influence of long-term tacrolimus treatment on cognitive function remains to be elucidated. Using a murine model of chronic tacrolimus neurotoxicity, we evaluated the effects of tacrolimus on cognitive function, synaptic balance, its regulating protein (Klotho), and oxidative stress in the hippocampus. Compared to vehicle-treated mice, tacrolimus-treated mice showed significantly decreased hippocampal-dependent spatial learning and memory function. Furthermore, tacrolimus caused synaptic imbalance, as demonstrated by decreased excitatory synapses and increased inhibitory synapses, and downregulated Klotho in a dose-dependent manner; the downregulation of Klotho was localized to excitatory hippocampal synapses. Moreover, tacrolimus increased oxidative stress and was associated with activation of the PI3K/AKT pathway in the hippocampus. These results indicate that tacrolimus impairs cognitive function via synaptic imbalance, and that these processes are associated with Klotho downregulation at synapses through tacrolimus-induced oxidative stress in the hippocampus.

长期他克莫司治疗对认知功能的影响仍有待阐明。使用慢性他克莫司神经毒性的小鼠模型，我们评估了他克莫司对认知功能、突触平衡、其调节蛋白 (Klotho) 和海马氧化应激的影响。与载体处理的小鼠相比，他克莫司处理的小鼠显示出海马依赖性空间学习和记忆功能显着降低。此外，他克莫司引起突触失衡，表现为兴奋性突触减少和抑制性突触增加，并以剂量​​依赖性方式下调 Klotho。Klotho 的下调定位于兴奋性海马突触。此外，他克莫司增加了氧化应激，并与海马中 PI3K/AKT 通路的激活有关。