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Simvastatin ameliorates synaptic plasticity impairment in chronic mild stress-induced depressed mice by modulating hippocampal NMDA receptor

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Abstract

Background

In our previous study, we showed simvastatin exerts an antidepressant effect and inhibits neuroinflammation. Given the role of synaptic impairment in depression development, we investigate the effect of simvastatin on synaptic plasticity in depression and the related mechanisms.

Methods

Electrophysiological analysis, Golgi staining, and transmission electron microscope were performed to analyze the effect of simvastatin on synaptic impairment in depression. In addition, the localization and reactivity of N-methyl-D-aspartate receptor (NMDAR) subunits and the downstream signaling were investigated to explore the mechanism of simvastatin’s effect on synaptic plasticity.

Results

Simvastatin ameliorated the reduction of the magnitude of long-term potentiation (LTP) in Schaffer collateral-CA1, restored hippocampal dendritic spine density loss, improved the number of spine synapses, reversed the reduction in BrdU-positive cells in chronic mild stress (CMS)-induced depressed mice, and ameliorated NMDA-induced neurotoxicity in hippocampal neurons. Dysfunction of NMDAR activity in the hippocampus is associated with depression. Simvastatin treatment reversed the surface expression and phosphorylation changes of NMDAR subunits in NMDA-treated hippocampal neurons and depressed mice. In addition, simvastatin further increased the levels of mature BDNF, activating TrkB-Akt-mTOR signaling, which is critical for synaptic plasticity.

Conclusions

These findings suggest that simvastatin can improve the dysfunction of NMDAR and ameliorate hippocampal synaptic plasticity impairment in depressed mice.

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Data Availability

The data that support the findings of study are available from the corresponding author upon reasonable request.

Abbreviations

NMDAR:

N-methyl-D-aspartate receptor

NR1:

N-methyl-D-aspartate receptor subunit 1

NR2A:

N-methyl-D-aspartate receptor subunit 2A

NR2B:

N-methyl-D-aspartate receptor subunit 2B

LTP:

Long-term potentiation

CMS:

Chronic mild stress

FST:

Forced swimming test

TST:

Tail suspension test

SPT:

Sucrose preference test

EPMT:

Elevated plus-maze test

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Funding

This work was supported by grants from the “Natural Science Foundation of Zhejiang Province” (LQ20H310003) and the “Natural Science Foundation of China” (82104145).

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Author notes

  1. Xu-Ben Yu and Kai-Long Zhong contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Chonnam National University, Gwangju, South Korea

    Xu-Ben Yu & Kwonseop Kim

  2. Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China

    Xu-Ben Yu

  3. School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China

    Xu-Ben Yu, Chuang Chen & Jing Fu

  4. Department of Pharmacy, Xiamen Clinical Research Center for Cancer Therapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, People’s Republic of China

    Kai-Long Zhong

  5. Department of Pharmacy, The First Affiliated Hospital of Xiamen University, Xiamen, 361005, People’s Republic of China

    Fang Chen

  6. Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China

    Hong-Min Zhou & Jing-Ye Pan

  7. Clinical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China

    Xiu-Hua Zhang

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  1. Xu-Ben Yu
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  3. Chuang Chen
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Contributions

X.H.Z. and J.Y.P. conceptualized and planned the work that led to the manuscript. X.B.Y., C.C., J.F., F.C., and H.M.Z. contributed to the acquisition of data and interpreted data. X.B.Y., C.C., and J.F. analyzed the data and provided statistical expertise. X.B.Y., K.K., and X.H.Z. drafted the manuscript. K.L.Z., X.B.Y., K.K., X.H.Z., and J.Y.P. revised the manuscript.

Corresponding authors

Correspondence to Xu-Ben Yu, Kwonseop Kim or Jing-Ye Pan.

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Yu, XB., Zhong, KL., Chen, C. et al. Simvastatin ameliorates synaptic plasticity impairment in chronic mild stress-induced depressed mice by modulating hippocampal NMDA receptor. Psychopharmacology 241, 75–88 (2024). https://doi.org/10.1007/s00213-023-06464-x

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