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Stress-Activated Protein Kinase JNK Modulates Depression-like Behaviors in Mice

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Abstract

Stress is considered as a major cause of depression. C-Jun N-terminal kinase (JNK) is a member of the stress-induced mitogen activated protein (MAP) kinase family which is often activated through phosphorylation. Clinical studies and animal experiments have found that abnormal phosphorylation/activation of JNK exists in the occurrence of various psychiatric diseases. Recently, several studies linked JNK kinase activity to depression. However, whether excessive activation of JNK activity is directly responsible for the occurrence of depression and the underlying mechanisms remain unclear. Here, we constructed a conditional transgenic mouse which is specifically expressing MKK7-JNK1 (CAJNK1) in the central nervous system. CAJNK1 mice showed activation of JNK and lead to depression-like behavior in mice. Transcriptome analysis indicates reduced expression of synaptic-associated genes in CAJNK1 mice brains. Consistently, we found abnormal dendritic spine development and PSD95 downregulation in CAJNK1 hippocampal neurons. Our studies provide compelling evidence that activation of JNK as an intrinsic factor leading to depression-like behavior in mice provides direct clues for targeting the JNK activity as a potential therapeutic strategy for depression.

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Data availability

The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr Axel Behrens for conditional CAJNK1 mice and Dr. Yi Zuo for Thy1-GFPm transgenic mice. We also want to thank Shuyuan Wang from Public Technology Service Center of Fujian Medical University for the technical assistance.

Funding

This work was supported by the National Science Foundation of China (31970920 and 81901168), National Science Foundation of Hunan Province under Grant 2022JJ4689, and the Special Fund for Science and Technology Innovation of Fujian Agriculture and Forestry University (CXZX2020089A).

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Author notes

  1. Xiaokun Zhou and Wenxiang Yi contributed equally to this study.

Authors and Affiliations

  1. Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, 350005, China

    Xiaokun Zhou, Wenxiang Yi, Yiqiang Zhi, Jurui Yu, Zhousong Luo & Dan Xu

  2. College of Biological Science and Engineering, Institute of Life Sciences, Fuzhou University, Fuzhou, 350108, China

    Xiaokun Zhou, Yiqiang Zhi & Jurui Yu

  3. School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350108, China

    Wenxiang Yi

  4. College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China

    Danping Lu & Liyu Chen

  5. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410028, China

    Ling Yuan

  6. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China

    Zhiheng Xu

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  1. Xiaokun Zhou
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Contributions

DX conceived and designed the project. XK Z performed most of the experiments and data analysis. WX Y performed RNAseq and dendritic spine analysis. YQ Z and JR Y help with tissue staining and data analysis. DX and XK Z wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhiheng Xu or Dan Xu.

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Ethics approval

All animal procedures used in this study were performed according to protocols approved by the Institutional Animal Care and Use Committee of Fujian Medical University (protocol number: FJMUIACUC 2021-J-0164).

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The authors declare no competing interests.

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Zhou, X., Yi, W., Zhi, Y. et al. Stress-Activated Protein Kinase JNK Modulates Depression-like Behaviors in Mice. Mol Neurobiol 60, 2367–2378 (2023). https://doi.org/10.1007/s12035-023-03209-x

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