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Chronic stress impairs the aquaporin-4-mediated glymphatic transport through glucocorticoid signaling

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Abstract

Background

The glymphatic system has recently been proposed to function as a brain-wide macroscopic system for the clearance of potentially harmful molecules, such as amyloid beta (e.g., Aβ), from the brain parenchyma. Previous literatures have established that the glymphatic function is dramatically suppressed by aging, traumatic brain injury, and some diseases. However, the effect of chronic stress on the glymphatic function and its underlying mechanism remains largely unknown.

Methods

Adult mice were randomly divided into four groups: chronic unpredictable mild stress (CUMS)–treated group, CUMS simultaneously treated with mifepristone (MFP) group, dexamethasone (DEX)-treated group, and control group. Stress response was observed by assessing the change of body weight, plasma corticosterone level, and behavior tests. The level of Aβ42 in cerebral tissue was assessed by ELISA. The glymphatic function was determined by using fluorescence tracer injection. The expression and localization of aquaporin-4 (AQP4) were evaluated by immunohistochemistry and western blot. The transcription level of AQP4 and anchoring molecules was evaluated by real-time PCR.

Findings

Compared with control group, CUMS-treated mice exhibited the impairment of global glymphatic function especially in the anterior brain. This change was accompanied by the decreased expression and polarization of AQP4, reduced transcription of AQP4, agrin, laminin, and dystroglycan in the anterior cortex. Similarly, the glucocorticoid receptor (GR) agonist DEX exposure could reduce the glymphatic function and AQP4 expression. Moreover, the GR antagonist MFP treatment could significantly rescue the glymphatic function and reverse the expression and polarization of AQP4 impaired by CUMS.

Conclusion

Chronic stress could impair the AQP4-mediated glymphatic transport in the brain through glucocorticoid signaling. Our results also suggest that GR antagonist could be beneficial to rescue the glymphatic function suppressed by chronic stress.

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Abbreviations

CUMS:

Chronic unpredictable mild stress

AQP4:

Aquaporin-4

CSF:

Cerebrospinal fluid

SAS:

Subarachnoid space

ISF:

Interstitial fluid

MFP:

Mifepristone

DEX:

Dexamethasone

PVS:

Paravascular space

Aβ:

β-Amyloid

GR:

Glucocorticoid receptor

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Funding

This study was supported by the National Natural Science Foundation of China (31871167), China Postdoctoral Science Foundation (No. 2016M601882), Postdoctoral Science Foundation of Jiangsu Province, China (No.1601083C), Suzhou Science and Technology Research Project (No. SYS201669), and Priority Academic Program Development of Jiangsu Higher Education Institutions.

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  1. Fang Wei and Jian Song contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Neurobiology, Medical College of Soochow University, 199 Ren-Ai Road, Suzhou, 215123, People’s Republic of China

    Fang Wei, Jian Song, Cui Zhang, Rong Xue, Li-Dong Shan, Shan Gong, Guo-Xing Zhang & Lin-Hui Wang

  2. Department of Orthopaedics, The first affiliated hospital of Soochow University, 188 Shi-Zi Street, Suzhou, 215006, People’s Republic of China

    Jun Lin

  3. Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Pharmacy, Suzhou, 215123, People’s Republic of China

    Zheng-Hong Qin

  4. Institute of Neuroscience, Soochow University, 199 Ren-Ai Road, Suzhou, 215123, People’s Republic of China

    Guang-Yin Xu

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  1. Fang Wei
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Correspondence to Lin-Hui Wang.

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All experiments were conducted in accordance with the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Council of Europe No. 123, Strasbourg 1985), and all experimental protocols were approved by the Institutional Animal Care and Use Committee of Soochow University.

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Wei, F., Song, J., Zhang, C. et al. Chronic stress impairs the aquaporin-4-mediated glymphatic transport through glucocorticoid signaling. Psychopharmacology 236, 1367–1384 (2019). https://doi.org/10.1007/s00213-018-5147-6

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