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ATF6β Deficiency Elicits Anxiety-like Behavior and Hyperactivity Under Stress Conditions

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Abstract

Activating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER) stress-regulated transcription factor that induces expression of major molecular chaperones in the ER. We recently reported that ATF6β, a subtype of ATF6, promoted survival of hippocampal neurons exposed to ER stress and excitotoxicity, at least in part by inducing expression of calreticulin, an ER molecular chaperone with high Ca2+-binding capacity. In the present study, we demonstrate that ATF6β deficiency in mice also decreases calreticulin expression and increases expression of glucose-regulated protein 78, another ER molecular chaperone, in emotional brain regions such as the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala. Comprehensive behavioral analyses revealed that Atf6b−/− mice exhibit anxiety-like behavior in the light/dark transition test and hyperactivity in the forced swim test. Consistent with these results, PFC and hypothalamic corticotropin-releasing hormone (CRH) expression was increased in Atf6b−/− mice, as was circulating corticosterone. Moreover, CRH receptor 1 antagonism alleviated anxiety-like behavior in Atf6b−/− mice. These findings suggest that ATF6β deficiency produces anxiety-like behavior and hyperactivity via a CRH receptor 1-dependent mechanism. ATF6β could play a role in psychiatric conditions in the emotional centers of the brain.

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Data Availability

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

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Acknowledgements

We thank S. Muramoto (Kanazawa Medical University) for support with the experiments. We would also like to thank Drs. Y. Ishigaki, H. Nishizono, and Y. Kaneko (Animal Resources and Genetic Engineering Center, Kanazawa Medical University) for technical assistance with Atf6b−/− mice.

Funding

This work was supported in part by JSPS KAKENHI (Grant Numbers JP17K13079 and JP20K11222) and by AMED (Grant Number JP20gm1410005s0301).

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Authors and Affiliations

  1. Studies in Rehabilitation, Graduate School of Health Sciences, Kumamoto Health Science University, Kumamoto, Japan

    Takashi Tanaka

  2. Department of Anatomy II, Kanazawa Medical University, Ishikawa, Japan

    Takashi Tanaka

  3. Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, 13- 1 Takara-Machi, 920-8640, Kanazawa, Ishikawa, Japan

    Dinh Thi Nguyen, Nichakarn Kwankaew, Hiroshi Ishii, Mika Takarada-Iemata, Tsuyoshi Hattori & Osamu Hori

  4. Department of Rehabilitation, Kyushu University of Nursing and Social Welfare, Kumamoto, Japan

    Megumi Sumizono

  5. School of Medicine, Kanazawa Medical University, Ishikawa, Japan

    Reika Shinoda

  6. Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan

    Seiichi Oyadomari

  7. Department of Physiology I, Kanazawa Medical University, Ishikawa, Japan

    Nobuo Kato

  8. Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan

    Kazutoshi Mori

  9. Department of Human Anatomy, Hanoi Medical University, Hanoi, Vietnam

    Dinh Thi Nguyen

  10. Division of Molecular Biology, Department of Medical Sciences, Faculty of Medicine, Bangkokthonburi University, Bangkok, Thailand

    Nichakarn Kwankaew

Authors
  1. Takashi Tanaka
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Contributions

Takashi Tanaka conceived the project, designed and performed all behavioral tests and ELISAs, analyzed the data, and wrote the manuscript. Dinh Thi Nguyen, Nichakarn Kwankaew, Hiroshi Ishii, Mika Takarada-Iemata, and Tsuyoshi Hattori performed in situ hybridization, RT-qPCR studies, and immunohistochemistry experiments. Megumi Sumizono conducted statistical analyses. Reika Shinoda performed genotyping of Atf6b−/− mice. Nobuo Kato supported experiments. Seiichi Oyadomari and Kazutoshi Mori provided Atf6b−/− mice. Osamu Hori searched the literature, wrote the manuscript, and supervised the project. All authors read and approved the final manuscript.

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Correspondence to Osamu Hori.

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Tanaka, T., Nguyen, D.T., Kwankaew, N. et al. ATF6β Deficiency Elicits Anxiety-like Behavior and Hyperactivity Under Stress Conditions. Neurochem Res 48, 2175–2186 (2023). https://doi.org/10.1007/s11064-023-03900-4

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