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Research Article
CHUL WOO YANG
Catholic University of Korea College of Medicine: Catholic University of Korea School of Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9796-636X
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The influence of long-term tacrolimus treatment on cognitive function remains to be elucidated. Using chronic tacrolimus neurotoxicity in mice, we evaluated the influence 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; its downregulation was localized to excitatory hippocampal synapses. Moreover, tacrolimus increased oxidative stress and was associated with the activation of the PI3K/AKT pathway in the hippocampus. The present 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.
Keywords
Klotho, Cognitive dysfunction, Tacrolimus, Synaptic imbalance, Oxidative stress, Hippocampus
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Subject Areas
Neurobiology of Disease
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This preprint is under consideration at Molecular Neurobiology. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
CHUL WOO YANG
Catholic University of Korea College of Medicine: Catholic University of Korea School of Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9796-636X
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 10 Mar, 2021
No community comments so far
Review #? received
Received 14 Mar, 2021
Reviewers invited
Invitations sent on 14 Mar, 2021
Editor invited
On 03 Mar, 2021
Editor assigned
On 28 Feb, 2021
First submitted
On 25 Feb, 2021
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
The influence of long-term tacrolimus treatment on cognitive function remains to be elucidated. Using chronic tacrolimus neurotoxicity in mice, we evaluated the influence 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; its downregulation was localized to excitatory hippocampal synapses. Moreover, tacrolimus increased oxidative stress and was associated with the activation of the PI3K/AKT pathway in the hippocampus. The present 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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
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