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Corticosterone Induced the Increase of proBDNF in Primary Hippocampal Neurons Via Endoplasmic Reticulum Stress

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Abstract

Major depression disorder is one of the most common psychiatric disorders that greatly threaten the mental health of a large population worldwide. Previous studies have shown that endoplasmic reticulum (ER) stress plays an important role in the pathophysiology of depression, and current research suggests that brain-derived neurotrophic factor precursor (proBDNF) is involved in the development of depression. However, the relationship between ER and proBDNF in the pathophysiology of depression is not well elucidated. Here, we treated primary hippocampal neurons of mice with corticosterone (CORT) and evaluated the relationship between proBDNF and ERS. Our results showed that CORT induced ERS and upregulated the expression of proBDNF and its receptor, Follistatin-like protein 4 (FSTL4), which contributed to significantly decreased neuronal viability and expression of synaptic-related proteins including NR2A, PSD95, and SYN. Anti-proBDNF neutralization and ISRIB (an inhibitor of the ERS) treatment, respectively, protected neuronal viabilities and increased the expression of synaptic-related proteins in corticosterone-exposed neurons. ISRIB treatment reduced the expression of proBDNF and FSTL4, whereas anti-proBDNF treatment did not affect ERS markers (Grp78, p-PERK, ATF4) expression. Our study presented evidence that CORT-induced ERS negatively regulated the neuronal viability and the level of synaptic-related protein of primary neurons via the proBDNF/FSTL4 pathway.

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There is no additional data, software, database, or application/tool available apart from that reported in the present study. All data is provided in the manuscript.

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Acknowledgments

We would like to thank Shanghai Yile Biotechnology Corp. for providing the monoclonal anti-proBDNF antibody.

Funding

This research was supported by the National Natural Science Foundation of China (31371212 to Chang-Qi Li; 81760238 and 81571256 to Fang-Fang Bi; 81771354 and 81471106 to Ru-Ping Dai; 81471372 to Fang Li; 81901231 to Zhao-Lan Hu) and by the Natural Science Foundation of Hunan Province, China (2018JJ3635 to Fang Li; 2019JJ40369 to Chang-Qi Li), and Graduate Research and Innovation Projects of Central South University, Changsha, Hunan, China (506021710 to Yu Liu; 506021717 to Guangjing Zou).

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  1. Yu Liu and Guang-Jing Zou contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Tongzipo Road 172, Changsha, 410013, Hunan, China

    Yu Liu, Guang-Jing Zou, Bo-Xuan Tu, Yan-Hui Cui, Fang Li & Chang-Qi Li

  2. Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China

    Zhao-Lan Hu, Cong Luo & Ru-Ping Dai

  3. Institute of Neuroscience, Medical College, University of South China, Hengyang, 421001, Hunan, China

    Yang Xu

  4. Department of Neurology, Xiang Ya Hospital, Central South University, Changsha, 410008, Hunan, China

    Fang-Fang Bi

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  1. Yu Liu
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Contributions

LY and ZGJ contributed to the cellular and molecular experiments, and helped write the manuscript. TBX contributed to the cellular experiments and the molecular experiments and editing of the manuscript. HZL and Luo C contributed to cellular experiments. CYH and XY contributed to the molecular experiments. LF and DRP contributed to data analysis. BFF and LCQ contributed to experimental design, data analysis, figure construction, and manuscript writing. All authors read and agreed to the final version of the manuscript.

Corresponding authors

Correspondence to Fang-Fang Bi or Chang-Qi Li.

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All animal experiments were approved by the Animal Care and Use Committee of Central South University in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (no. 2019-s08).

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Liu, Y., Zou, GJ., Tu, BX. et al. Corticosterone Induced the Increase of proBDNF in Primary Hippocampal Neurons Via Endoplasmic Reticulum Stress. Neurotox Res 38, 370–384 (2020). https://doi.org/10.1007/s12640-020-00201-4

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