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Anti-depressive-like behaviors of APN KO mice involve Trkb/BDNF signaling related neuroinflammatory changes

Molecular Psychiatry volume 27, pages 1047–1058 (2022)Cite this article

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Abstract

Major depression disorder is a severe mental illness often linked with metabolic disorders. Adiponectin is an adipocyte-secreted circulatory hormone with antidiabetic and glucose/lipid modulation capacities. Studies have demonstrated the pathophysiological roles of adiponectin involved in various neurological disorders, including depression. However, the underlying mechanisms are poorly understood. Here we showed that adiponectin deprivation enhanced antidepressive-like behaviors in the LPS-induced model of depression. APN KO mice displayed increased cytokines (both pro and anti-inflammatory), accompanied by an impaired expression of adiponectin receptors (mRNA/protein level) and decreasing IBA-1 level in the cortex and primary microglia of LPS treated APN KO mice. Further, LPS-treatment significantly reduced p-NFκB expression in the microglia of APN KO mice. However, the Bay11-7082 treatment recovered p-NFκB expression in the cortex of APN KO mice in the presence of LPS. Interestingly, the antidepressant potentials of APN KO mice were abolished by TrkB antagonist K252a, IKK inhibitor Bay11-7082, and AdipoRon suggesting crosstalk between TrkB/BDNF signaling and NFκB in depression. Furthermore, the effects of Bay11-7082 were abolished by a TrkB/BDNF activator (7,8-DHF), indicating a critical role of TrkB/BDNF signaling. Taken together, these findings showed that dysregulated neuroinflammatory status and BDNF signaling might underlie the antidepressive-like behaviors of APN KO mice. NFκB elicited BDNF changes may be accountable for the pathogenesis of LPS induced depression, where APN might present an alternative therapeutic target for depressive disorders.

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Fig. 1: LPS-treatment did not enhance depressive-like behaviors and Iba-1, while modified cytokines level in APN KO mice.
Fig. 2: LPS-treatment to PMG of APN KO mice.
Fig. 3: LPS-treated APN KO mice lost anti-depressive-like behaviors and modified BNDF/TrkB and synaptic gene expression upon K252a, Bay11-7082, and AR treatment.
Fig. 4: 7,8-DHF reversed Bay11-7082 modified changes in the LPS-treated APN KO mice.
Fig. 5: APN receptors expression in APN KO mice, PMG, and BV2 cells.

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Acknowledgements

Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China. This work was supported by Grants Science and Technology Innovation Committee of Shenzhen No: JCYJ20170810163329510; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions No: 2019SHIBS0004; Sanming Project of Medicine in Shenzhen (No. SZSM201911003) Shenzhen Key Medical Discipline Construction Fund (No.SZXK06162); Shenzhen bay laboratory NO:SZBL2019062801003.

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Authors and Affiliations

  1. State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China

    Weifen Li, Tahir Ali, Chengyou Zheng, Kaiwu He, Zizhen Liu, Fawad Ali Shah & Shupeng Li

  2. Riphah Institute of Pharmaceutical Sciences Riphah International University Islamabad, Islamabad, Pakistan

    Fawad Ali Shah

  3. Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China

    Ningning Li

  4. Tomas Lindahl Nobel Laureate Laboratory, Precision Medicine Research Centre, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China

    Ningning Li

  5. Department of Infectious Diseases and Shenzhen key laboratory for endogenous infections, the 6th Affiliated Hospital of Shenzhen University Health Science Center. No 89, Taoyuan Road, Nanshan District, Shenzhen, 518052, China

    Zhi-Jian Yu

  6. Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Shupeng Li

  7. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Shupeng Li

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WL designed and performed the experiments, TA data analysis, wrote the manuscript, Chengyou Zheng, Kaiwu He, and Zizhen Liu helped in the experiment; Fawad Ali Shah, Ningning Li, and Zhi-Jian Yu helped in manuscript, experimental tools and supported the study. SL endorsed the study, corresponding authors, reviewed and approved the manuscript, and held all the responsibilities related to this manuscript. All authors reviewed and approved the manuscript.

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Li, W., Ali, T., Zheng, C. et al. Anti-depressive-like behaviors of APN KO mice involve Trkb/BDNF signaling related neuroinflammatory changes. Mol Psychiatry 27, 1047–1058 (2022). https://doi.org/10.1038/s41380-021-01327-3

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