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Glucocorticoid receptor activation induces decrease of hippocampal astrocyte number in rats

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Abstract

Rationale

The decrease of astrocyte number and hypothalamic-pituitary-adrenal (HPA) axis overactivity are observed in individuals with major depressive disorder. Elevated levels of glucocorticoids induced by hyperactivation of the HPA axis may result in glucocorticoid receptor (GR) activation. However, it is unclear whether there is a direct link between GR activation and the decrease of astrocyte number.

Methods

Animals were exposed to chronic unpredictable stress (CUS) for 28 days and treated with continuous subcutaneous injections of vehicle or corticosterone (CORT; 40 mg/kg/day) for 21 days. We then administered mifepristone on day 21 after CUS and on day 18 after the CORT treatment. We observed behavioral deficits in the sucrose preference test, open field test, and forced swim test. Protein expression was analyzed using immunofluorescence (IF) and western blot (WB).

Results

Animals exposed to CUS exhibited behavioral deficits in tests measuring anhedonia, anxiety, and despair state. They also had decreases in glial fibrillary acidic protein (GFAP) expression and numbers of GFAP-positive cells in the hippocampus. The behavioral and cellular alterations induced by CUS were reversed by subchronic treatment with the GR antagonist mifepristone. We also found that the subcutaneous injection of glucocorticoids may induce depression-like behavior and reduce GFAP protein expression in rats, which was similarly reversed by mifepristone.

Conclusions

These findings provide experimental evidence that GR activation due to elevated CORT levels induces the decrease of hippocampal astrocyte number in rats.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81573636, 81773924, U1402221, 81560663), Beijing Natural Science Foundation (7182114), PUMC Youth Fund (3332016058), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-004), the Scientific Research Foundation of the Higher Education Institutions of Hunan Province (15K091), Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (BZ0150), PUMC Graduate Education and Teaching Reform Project (10023201600801), The State Key Laboratory Fund Open Project (GTZK201610), and China Postdoctoral Science Foundation (2013M540066).

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Authors and Affiliations

  1. Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China

    Yu-Xia Lou & Nai-Hong Chen

  2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Jing Li, Zhen-Zhen Wang, Cong-Yuan Xia & Nai-Hong Chen

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  1. Yu-Xia Lou
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  2. Jing Li
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Correspondence to Nai-Hong Chen.

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Lou, YX., Li, J., Wang, ZZ. et al. Glucocorticoid receptor activation induces decrease of hippocampal astrocyte number in rats. Psychopharmacology 235, 2529–2540 (2018). https://doi.org/10.1007/s00213-018-4936-2

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