Tacrolimus Decreases Cognitive Function by Impairing Hippocampal Synaptic Balance: a Possible Role of Klotho

• Published in: Molecular neurobiology 2021-11, Vol.58 (11), p.5954-5970
• Main Authors: Shin, Yoo Jin, Lim, Sun Woo, Cui, Sheng, Ko, Eun Jeong, Chung, Byung Ha, Kim, Hong Lim, Riew, Tae Ryong, Lee, Mun Yong, Yang, Chul Woo
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cognition Disorders - chemically induced; Cognition Disorders - metabolism; Cognitive ability; Dendrites - metabolism; Down-Regulation - drug effects; Hippocampus; Hippocampus - pathology; Hippocampus - physiopathology; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - toxicity; Klotho protein; Klotho Proteins - biosynthesis; Klotho Proteins - genetics; Klotho Proteins - physiology; Male; Maze Learning; Mice; Mice, Inbred BALB C; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurobiology; Neurology; Neurosciences; Neurotoxicity; Open Field Test; Oxidative stress; Oxidative Stress - drug effects; Phosphatidylinositol 3-Kinases - physiology; Proto-Oncogene Proteins c-akt - physiology; Random Allocation; Signal Transduction; Spatial discrimination learning; Spatial Learning; Spatial Memory; Synapses; Synapses - drug effects; Synapses - physiology; Tacrolimus; Tacrolimus - pharmacology; Tacrolimus - toxicity
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-021-02499-3

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.