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Chronic N-acetylcysteine treatment alleviates acute lipopolysaccharide-induced working memory deficit through upregulating caveolin-1 and synaptophysin in mice

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Abstract

Rationale

Working memory (WM) is a dynamic encoding process and an active representation of information over a short time. The ability to guide forthcoming behavior would be disrupted if WM was impaired by various factors including inflammation, stress, free radicals, and disease states such as schizophrenia. However, the mechanism underlying acute working memory impairment remains to be defined.

Objectives

In this study, we tested the hypothesis that decreased caveolin-1 (Cav-1) and synaptophysin (SYP) accounted for the WM impairment challenged with acute intraperitoneally lipopolysaccharide (LPS), which mimicked neuroinflammation. Delayed alternation T-maze task (DAT) was used to assess working memory of adult male C57BL/6 mice, and western blot and immunostaining were used to detect protein expression and distribution in medial prefrontal cortex (mPFC) and hippocampus.

Results

Our results showed that LPS dose-dependently induced working memory deficit accompanied by the decrease of Cav-1 and SYP in mPFC but not hippocampus. In addition, LPS significantly decreased protein level of Cav-1 and SYP in neurons by activating microglia cells. More important, 2-week N-acetylcysteine (NAC) treatment dose-dependently inhibited LPS-induced working memory deficit by improving the ability to use Lose-shift but not Win-shift strategy and significantly inhibited LPS-induced downregulation of Cav-1 and SYP in mPFC.

Conclusions

Taken together, our findings demonstrate that chronic NAC treatment alleviates acute LPS-induced working memory deficit through upregulating Cav-1 and SYP in mice.

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Abbreviations

BDL:

Bile duct ligation;

Cav-1:

Caveolin-1

DAT:

Delayed alternation T-maze task

IL-1β:

Interleukine-1 beta

i.p.:

Intraperitoneally

LCM:

LPS-conditioned medium

LPS:

lipopolysaccharide

mPFC:

Medial prefrontal cortex

NAC:

N-acetylcysteine

ROS:

Reactive oxygen series

SYP:

Synaptophysin

TNF-α:

Tumor necrosis factor-α

WM:

Working memory

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Funding

This work was supported, by the National Natural Science Foundation of China (81701316, 81371224, 81671145), by the Natural Science Foundation of Jiangsu Province of China (L221506415, BK20140366), and by the Open Research Fund of State Key Laboratory of Bioelectronics, Southeast University (No. 7). This work was also partly supported by Priority Academic Program Development of Jiangsu Higher Education Institutions of China.

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Author notes

  1. Xianzhi Shen and Yanyun Sun contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

    Xianzhi Shen, Yanyun Sun, Mengwei Wang, Hui Shu, Li-Juan Zhu & Xinchun Jin

  2. School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China

    Xianzhi Shen & Xinchun Jin

  3. School of Medicine, Ningbo University, Ningbo, 315211, China

    Pei-Yun Yan & Jun-Fang Zhang

  4. Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo, 315211, China

    Jun-Fang Zhang

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  1. Xianzhi Shen
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  2. Yanyun Sun
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  3. Mengwei Wang
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  4. Hui Shu
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  7. Jun-Fang Zhang
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Contributions

This work was performed and accomplished by all authors. XS, YS, MW, HS, LJZ, and PY contributed to the execution of the entire research project and the statistical analyses. XS, JZ, and XJ wrote the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Jun-Fang Zhang or Xinchun Jin.

Ethics declarations

All experimental procedures were approved by the University Committee on Animal Care of Soochow University and performed according to the NIH Guide for the Care and Use of Laboratory Animals.

Conflicts of interest

The authors declare that they have no conflicts of interest.

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Shen, X., Sun, Y., Wang, M. et al. Chronic N-acetylcysteine treatment alleviates acute lipopolysaccharide-induced working memory deficit through upregulating caveolin-1 and synaptophysin in mice. Psychopharmacology 235, 179–191 (2018). https://doi.org/10.1007/s00213-017-4762-y

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