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Theranostics 2023; 13(3):955-972. doi:10.7150/thno.76553 This issue Cite

Research Paper

Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC

Chenchen Li1*, Bo Liu1,2*, Jingyi Xu1*, Bin Jing3*, Lijie Guo1, Liyong Wang4, Milin Wang1, Haochen Zhang1, Qianqian He1, Xin Yu1, Yan Zhang5, Zhi-Qing David Xu1,6✉, Yutao Yang1✉

1. Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
2. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
3. School of Biomedical Engineering, Capital Medical University, Beijing,100069, China.
4. Central lab, Capital Medical University, Beijing, 100069, China.
5. Sports & Medicine Integration Research Center, Capital University of Physical Education and Sports, Beijing, 100086, China.
6. Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Yutao Yang (E-mail: yutaoyedu.cn) and Zhi-Qing David Xu (E-mail: zhiqingxedu.cn).

Citation:
Li C, Liu B, Xu J, Jing B, Guo L, Wang L, Wang M, Zhang H, He Q, Yu X, Zhang Y, Xu ZQD, Yang Y. Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC. Theranostics 2023; 13(3):955-972. doi:10.7150/thno.76553. https://www.thno.org/v13p0955.htm
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Abstract

Graphic abstract

Background: Stress is an important risk factor to induce psychiatric disorders such as depression. Phloretin (PHL), a natural dihydrochalcone compound, has been shown to exhibit anti-inflammatory and anti-oxidative effects. However, the impact of PHL on the depression and the underlying mechanism remain unclear.

Methods: The animal behavior tests were used to determine the protective of PHL on the chronic mild stress (CMS)-induced depression-like behaviors. The Magnetic Resonance Imaging (MRI), electron microscopy analysis, fiber photometry, electrophysiology, and Structure Illumination Microscopy (SIM) were used to investigate the protective of PHL on the structural and functional impairments induced by CMS exposure in the mPFC. The RNA sequencing, western blot, reporter gene assay, and chromatin immunoprecipitation were adopted to investigate the mechanisms.

Results: We showed that PHL efficiently prevented the CMS-induced depressive-like behaviors. Moreover, PHL not only attenuated the decrease of synapse losses but also improved the dendritic spine density and neuronal activity in the mPFC after CMS exposure. Furthermore, PHL remarkably inhibited the CMS-induced microglial activation and phagocytic activity in the mPFC. In addition, we demonstrated that PHL decreased the CMS-induced synapse losses by inhibiting the deposition of complement C3 deposition onto synapses and subsequent microglia-mediated synaptic engulfment. Finally, we revealed that PHL inhibited the NF-κB-C3 axis to display neuroprotective effects.

Conclusions: Our results indicate that PHL represses the NF-κB-C3 axis and subsequent microglia-mediated synaptic engulfment to protect against CMS-induced depression in the mPFC.

Keywords: Phloretin, stress, depression, microglia, synaptic engulfment

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APA
Li, C., Liu, B., Xu, J., Jing, B., Guo, L., Wang, L., Wang, M., Zhang, H., He, Q., Yu, X., Zhang, Y., Xu, Z.Q.D., Yang, Y. (2023). Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC. Theranostics, 13(3), 955-972. https://doi.org/10.7150/thno.76553.

ACS
Li, C.; Liu, B.; Xu, J.; Jing, B.; Guo, L.; Wang, L.; Wang, M.; Zhang, H.; He, Q.; Yu, X.; Zhang, Y.; Xu, Z.Q.D.; Yang, Y. Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC. Theranostics 2023, 13 (3), 955-972. DOI: 10.7150/thno.76553.

NLM
Li C, Liu B, Xu J, Jing B, Guo L, Wang L, Wang M, Zhang H, He Q, Yu X, Zhang Y, Xu ZQD, Yang Y. Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC. Theranostics 2023; 13(3):955-972. doi:10.7150/thno.76553. https://www.thno.org/v13p0955.htm

CSE
Li C, Liu B, Xu J, Jing B, Guo L, Wang L, Wang M, Zhang H, He Q, Yu X, Zhang Y, Xu ZQD, Yang Y. 2023. Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC. Theranostics. 13(3):955-972.

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