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Theranostics 2023; 13(3):1059-1075. doi:10.7150/thno.81067 This issue Cite

Research Paper

Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression

Kuo Zhang*, Fan Wang*, Mengying Zhai*, Meiyao He, Yuxuan Hu, Lijin Feng, Yuting Li, Jingyu Yang✉, Chunfu Wu✉

Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China.
* These authors contributed equally to this work.

✉ Corresponding authors: Chunfu Wu (wucfedu.cn), and Jingyu Yang (yangjingyuedu.cn), Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China.

Citation:
Zhang K, Wang F, Zhai M, He M, Hu Y, Feng L, Li Y, Yang J, Wu C. Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression. Theranostics 2023; 13(3):1059-1075. doi:10.7150/thno.81067. https://www.thno.org/v13p1059.htm
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Abstract

Graphic abstract

Background: Depression is a mental disorder that poses a serious threat to human health. Adult hippocampal neurogenesis (AHN) is closely associated with the efficacy of antidepressants. Chronic treatment with corticosterone (CORT), a well-validated pharmacological stressor, induces depressive-like behaviors and suppresses AHN in experimental animals. However, the possible mechanisms of chronic CORT action remain elusive.

Methods: A chronic CORT treatment (0.1 mg/mL, drinking water for 4 weeks) was applied to prepare a mouse model of depression. Immunofluorescence was performed to analyze the hippocampal neurogenesis lineage, and immunoblotting, immunofluorescence, electron microscopy, and adeno-associated virus (AAV) expressing a pH-sensitive tandemly tagged light chain 3 (LC3) protein were used to analyze neuronal autophagy. AAV-hSyn-miR30-shRNA was used to knock down autophagy-related gene 5 (Atg5) expression in the neurons.

Results: Chronic CORT induces depressive-like behaviors and decreases the expression of neuronal brain-derived neurotrophic factor (BDNF) in the dentate gyrus (DG) of the hippocampus in mice. Moreover, it markedly diminishes the proliferation of neural stem cells (NSCs), neural progenitor cells, and neuroblasts and impairs the survival and migration of newborn immature and mature neurons in the DG, which may be attributed to changes in the cell cycle kinetics and induction of NSCs apoptosis. Furthermore, chronic CORT induces hyperactive neuronal autophagy in the DG, possibly by increasing the expression of ATG5 and causing excess lysosomal degradation of BDNF in neurons. Notably, inhibiting hyperactive neuronal autophagy in the DG of mice by knocking down Atg5 in neurons using RNA interference reverses the decrease of neuronal BDNF expression, rescues AHN, and exerts antidepressant effects.

Conclusion: Our findings reveal a neuronal autophagy-dependent mechanism that links chronic CORT to reduced neuronal BDNF levels, AHN suppression and depressive-like behavior in mice. In addition, our results provide insights for treating depression by targeting neuronal autophagy in the DG of the hippocampus.

Keywords: Corticosterone, Depression, BDNF, Adult hippocampal neurogenesis, Neuronal autophagy.

Citation styles

APA
Zhang, K., Wang, F., Zhai, M., He, M., Hu, Y., Feng, L., Li, Y., Yang, J., Wu, C. (2023). Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression. Theranostics, 13(3), 1059-1075. https://doi.org/10.7150/thno.81067.

ACS
Zhang, K.; Wang, F.; Zhai, M.; He, M.; Hu, Y.; Feng, L.; Li, Y.; Yang, J.; Wu, C. Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression. Theranostics 2023, 13 (3), 1059-1075. DOI: 10.7150/thno.81067.

NLM
Zhang K, Wang F, Zhai M, He M, Hu Y, Feng L, Li Y, Yang J, Wu C. Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression. Theranostics 2023; 13(3):1059-1075. doi:10.7150/thno.81067. https://www.thno.org/v13p1059.htm

CSE
Zhang K, Wang F, Zhai M, He M, Hu Y, Feng L, Li Y, Yang J, Wu C. 2023. Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression. Theranostics. 13(3):1059-1075.

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