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NPTX2 is a key component in the regulation of anxiety

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Abstract

Anxiety disorders significantly impair quality of life. However, limited knowledge of the underlying mechanisms impedes the development of effective therapeutics. Previous studies have suggested that the expression of the Nptx2 gene is associated with anxiety, but the neurobiological processes underlying this association remain unclear. We generated multiple mouse models with knockout or overexpression of Nptx2 in specific brain regions and during different developmental stages to assess anxiety, adult neurogenesis, and glucocorticoid-related gene expression. Our results provide evidence that Nptx2 expression in the adult hippocampus regulates anxiety in mice. Eliminating Nptx2 expression in either the developing mouse brain or in adulthood leads to increased anxiety levels. The increase in anxiety was evident in hippocampus-specific Nptx2 knockout mice, but not in an amygdala specific knockouts. Gene expression analysis revealed increased expression of glucocorticoid receptor target genes in Nptx2 knockout mice after acute stress. Overexpression of Nptx2 in the hippocampus alleviates stress-induced anxious behaviors and reverses the changes in expression of glucocorticoid receptor related genes. In conclusion, we demonstrate that Nptx2 in the hippocampus performs a critical role in modulating anxiety, hippocampal cell proliferation, and glucocorticoid receptor related gene expression. Our results suggest Nptx2 may be a potential target for anxiolytic therapeutics.

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Acknowledgements

We would like to thank Dr. Roderick Carter (University of Edinburg, UK), Dr. Sagiv Shifman (The Hebrew University of Jerusalem, Israel), and Dr. David A. Keays (Research Institute of Molecular Pathology, Austria) for their helpful comments on this manuscript. Funding: This study was supported by grants from the Chang Gung Memorial Hospital (CMRPD1E0312) (to G-JH) and the Ministry of Science and Technology (MOST 105-2320-B-182-040) (to G-JH).

Author contributions

SC and G-JH conceived the study and wrote the manuscript. SC and PB conducted animal experiments and biochemical studies. C-YT performed blastocyst microinjection. G-JH performed the animal surgery. C-PS made the Nptx2 AAV viral vectors. HL performed RNA-seq experiment. JD contributed reporter mice and provided input on the manuscript.

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Author notes

    Affiliations

    1. Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

      • Simon Chang
      • , Philane Bok
      • , Hsuan Liu
      •  & Guo-Jen Huang
    2. Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany

      • Simon Chang
      •  & Jan M. Deussing
    3. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan

      • Ching-Yen Tsai
    4. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

      • Cheng-Pu Sun
    5. Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan

      • Hsuan Liu
    6. Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan

      • Guo-Jen Huang
    7. Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan

      • Guo-Jen Huang

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    Competing interests

    The authors declare no competing interests.

    Corresponding author

    Correspondence to Guo-Jen Huang.

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