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

Yoo Jin Shin; Sun Woo Lim; Sheng Cui; Eun Jeong Ko; Byung Ha Chung; Hong Lim Kim; Tae Ryong Riew; Mun Yong Lee; Chul Woo Yang

doi:10.1007/s12035-021-02499-3

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

Yoo Jin Shin, Sun Woo Lim, Sheng Cui, Eun Jeong Ko, Byung Ha Chung, Hong Lim Kim, Tae Ryong Riew, Mun Yong Lee, Chul Woo Yang

The Catholic University of Korea

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	5954-5970
Number of pages	17
Journal	Molecular Neurobiology
Volume	58
Issue number	11
DOIs	https://doi.org/10.1007/s12035-021-02499-3
State	Published - Nov 2021

Bibliographical note

Funding Information:
This work was supported by the Korean Health Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (HI14C3417), and the Basic Science Research Program through a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education (NRF-2018R1D1A1B07044219) and the Ministry of Science, ICT & Future Planning (NRF-2020R1A2C2012711).

Funding Information:
We thank all the administrative and research staff in the Transplantation Research Center, The College of Medicine, The Catholic University of Korea.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

Cognitive dysfunction
Hippocampus
Klotho
Oxidative stress
Synaptic imbalance
Tacrolimus

Access to Document

10.1007/s12035-021-02499-3

Cite this

@article{4a2694c9d5c54193848011d2b51dc8cd,

title = "Tacrolimus Decreases Cognitive Function by Impairing Hippocampal Synaptic Balance: a Possible Role of Klotho",

abstract = "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.",

keywords = "Cognitive dysfunction, Hippocampus, Klotho, Oxidative stress, Synaptic imbalance, Tacrolimus",

author = "Shin, {Yoo Jin} and Lim, {Sun Woo} and Sheng Cui and Ko, {Eun Jeong} and Chung, {Byung Ha} and Kim, {Hong Lim} and Riew, {Tae Ryong} and Lee, {Mun Yong} and Yang, {Chul Woo}",

note = "Funding Information: This work was supported by the Korean Health Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (HI14C3417), and the Basic Science Research Program through a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education (NRF-2018R1D1A1B07044219) and the Ministry of Science, ICT & Future Planning (NRF-2020R1A2C2012711). Funding Information: We thank all the administrative and research staff in the Transplantation Research Center, The College of Medicine, The Catholic University of Korea. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2021",

month = nov,

doi = "10.1007/s12035-021-02499-3",

language = "English",

volume = "58",

pages = "5954--5970",

journal = "Molecular Neurobiology",

issn = "0893-7648",

publisher = "Springer",

number = "11",

}

TY - JOUR

T1 - Tacrolimus Decreases Cognitive Function by Impairing Hippocampal Synaptic Balance

T2 - a Possible Role of Klotho

AU - Shin, Yoo Jin

AU - Lim, Sun Woo

AU - Cui, Sheng

AU - Ko, Eun Jeong

AU - Chung, Byung Ha

AU - Kim, Hong Lim

AU - Riew, Tae Ryong

AU - Lee, Mun Yong

AU - Yang, Chul Woo

N1 - Funding Information: This work was supported by the Korean Health Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (HI14C3417), and the Basic Science Research Program through a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education (NRF-2018R1D1A1B07044219) and the Ministry of Science, ICT & Future Planning (NRF-2020R1A2C2012711). Funding Information: We thank all the administrative and research staff in the Transplantation Research Center, The College of Medicine, The Catholic University of Korea. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

KW - Cognitive dysfunction

KW - Hippocampus

KW - Klotho

KW - Oxidative stress

KW - Synaptic imbalance

KW - Tacrolimus

UR - http://www.scopus.com/inward/record.url?scp=85113364479&partnerID=8YFLogxK

U2 - 10.1007/s12035-021-02499-3

DO - 10.1007/s12035-021-02499-3

M3 - Article

C2 - 34435330

AN - SCOPUS:85113364479

SN - 0893-7648

VL - 58

SP - 5954

EP - 5970

JO - Molecular Neurobiology

JF - Molecular Neurobiology

IS - 11

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this