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Astrocytic RARγ mediates hippocampal astrocytosis and neurogenesis deficits in chronic retinoic acid-induced depression

Neuropsychopharmacology (2024)Cite this article

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Abstract

Accumulating clinical evidence indicates that chronic exposure to retinoic acid (RA) may lead to depressive symptoms and even increase the risk of suicidal behavior, which severely limits the clinical long-term application of RA. The exact mechanisms through which RA contributes to the onset of depression remain largely unclear. Here, we administered intraperitoneal injections of all-trans RA to male C57BL/6 J mice over a period of 21 days. Mice subjected to chronic RA exposure displayed depressive-like behaviors, accompanied by impaired hippocampal neurogenesis and heightened RA receptor gamma (RARγ) levels in the ventral hippocampus (vHip). The administration of an RARγ antagonist effectively mitigated these RA-induced neurogenesis impairments and depressive-like behaviors. Chronic exposure to RA was also observed to promote hippocampal astrocytosis and increase astrocytic Rarγ expression in the ventral dentate gyrus (vDG) of hippocampus. Notably, astrocytic RARγ in the vDG was found to be a key factor in the observed hippocampal astrocytosis and neurogenesis impairments, and depressive-like behaviors. Chronic exposure to RA resulted in increased extracellular glutamate levels in neural stem cells (NSCs), accompanied by a decrease in glutamate transporter 1 (GLT-1) expression. Enhancing astrocytic GLT-1 expression was found to alleviate both hippocampal astrocytosis and depressive-like behaviors caused by RA. These findings underscore the critical role of astrocytic RARγ-GLT-1 axis in the development of hippocampal astrocytosis, neurogenesis impairments, and depressive symptoms, suggesting that targeting RARγ-GLT-1 could potentially offer an effective therapeutic approach for depression.

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Fig. 1: Chronic RA-induced depressive mice exhibit hippocampal neurogenesis deficits and upregulation of RARγ expression.
Fig. 2: RARγ antagonist, but not RARα or RARβ antagonist, effectively reverses hippocampal neurogenesis deficits in the RA-induced depressive mouse.
Fig. 3: Knocking down astrocytic RARγ alleviates RA-induced hippocampal astrocytosis, neurogenesis deficits and depressive-like behaviors.
Fig. 4: Overexpression of astrocytic RARγ directly induces hippocampal astrocytosis, neurogenesis deficits and depressive-like behaviors.
Fig. 5: Astrocytic RARγ induces hippocampal astrocytosis and depression by suppressing GLT-1 expression in the vDG.

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Data availability

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

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Acknowledgements

We thank Chunhua Yuan, Lirong Sun, Shuji Li, Yingying Fang, and Ting Guo (Southern Medical University) for their technical support.

Funding

The work was supported by the National Natural Science Foundation of China (81971234), Natural Science Foundation of Guangdong Province, China (2022A1515012248), the Key Area Research and Development Program of Guangdong Province (2018B030334001 and 2018B030340001), the Science and Technology Program of Guangzhou (202007030013), and Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders (2023B1212120004).

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Authors and Affiliations

  1. Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China

    Huixian Huang, Wensi Lu, Ran Luo, Yinyun Zeng, Xiaohong Su, Xinyi Zhang & Xuemin Wang

  2. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Yuqin Zhang

  3. Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Bo Tian

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Contributions

XMW and HXH designed the study and wrote the paper. BT reviewed and edited the manuscript. HXH analyzed the data. HXH performed most of the experiments with the help of WSL and RL. RL and YYZ performed the real-time quantitative PCR experiment. XHS performed some immunofluorescence experiments. YQZ was responsible for animal care. XYZ performed HPLC experiment with the help of YYZ. XMW and BT supervised all phases of the project.

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Correspondence to Bo Tian or Xuemin Wang.

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Huang, H., Lu, W., Luo, R. et al. Astrocytic RARγ mediates hippocampal astrocytosis and neurogenesis deficits in chronic retinoic acid-induced depression. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01983-3

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