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PSD-93 up-regulates the synaptic activity of corticotropin-releasing hormone neurons in the paraventricular nucleus in depression

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Abstract

Since the discovery of ketamine anti-depressant effects in last decade, it has effectively revitalized interest in investigating excitatory synapses hypothesis in the pathogenesis of depression. In the present study, we aimed to reveal the excitatory synaptic regulation of corticotropin-releasing hormone (CRH) neuron in the hypothalamus, which is the driving force in hypothalamic–pituitary–adrenal (HPA) axis regulation. This study constitutes the first observation of an increased density of PSD-93-CRH co-localized neurons in the hypothalamic paraventricular nucleus (PVN) of patients with major depression. PSD-93 overexpression in CRH neurons in the PVN induced depression-like behaviors in mice, accompanied by increased serum corticosterone level. PSD-93 knockdown relieved the depression-like phenotypes in a lipopolysaccharide (LPS)-induced depression model. Electrophysiological data showed that PSD-93 overexpression increased CRH neurons synaptic activity, while PSD-93 knockdown decreased CRH neurons synaptic activity. Furthermore, we found that LPS induced increased the release of glutamate from microglia to CRH neurons resulted in depression-like behaviors using fiber photometry recordings. Together, these results show that PSD-93 is involved in the pathogenesis of depression via increasing the synaptic activity of CRH neurons in the PVN, leading to the hyperactivity of the HPA axis that underlies depression-like behaviors.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (91732304 and 32030046), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB02030001 and XDB32020200). We are grateful to the Netherlands Brain Bank for providing human brain material and clinical details. We thank Dr. Zhi Zhang (USTC) for providing the Cx3cr1-CreERT2 mice.

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Author notes

  1. Xin-Ya Qin and Qing-Hong Shan have contributed equally to this work.

Authors and Affiliations

  1. Chinese Academy of Sciences Key Laboratory of Brain Function and Diseases, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Xin-Ya Qin, Qing-Hong Shan, Hui Fang, Yu Wang, Peng Chen & Jiang-Ning Zhou

  2. Institute of Brain Science, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

    Xin-Ya Qin, Qing-Hong Shan, Yu Wang, Peng Chen & Jiang-Ning Zhou

  3. Anhui Institute of Pediatric Research, Anhui Provincial Children’s Hospital, Hefei, Anhui, China

    Hui Fang

  4. Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Zhi-Qi Xiong

  5. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Zhi-Qi Xiong & Jiang-Ning Zhou

  6. Neuropsychiatric Disorders Group, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands

    Dick F. Swaab

Authors
  1. Xin-Ya Qin
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Contributions

J-NZ designed the studies. X-YQ and Q-HS performed most of the experiments and data analysis, and wrote the draft manuscript. HF, YW, and PC conducted some of the molecular experiments and behavioral experiments. Z-QX provided the plasmid. DS provided the human brain tissue and was involved in the revision of the manuscript. X-YQ and J-NZ wrote the paper.

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Correspondence to Jiang-Ning Zhou.

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Qin, XY., Shan, QH., Fang, H. et al. PSD-93 up-regulates the synaptic activity of corticotropin-releasing hormone neurons in the paraventricular nucleus in depression. Acta Neuropathol 142, 1045–1064 (2021). https://doi.org/10.1007/s00401-021-02371-7

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