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Mol. Psychiatr., Sep 20 2023 | https://doi.org/10.1038/s41380-023-02258-x Amphiregulin normalizes altered circuit connectivity for social dominance of the CRTC3 knockout mouse.

Ji-Seon Park^1,8, Hwon Heo^2,8, Min-Seok Kim³, Seung-Eun Lee³, Sukyoung Park⁴, Ki-Hyun Kim⁴, Young-Ho Kang⁴, Je Seong Kim⁴, Young Hoon Sung⁵, Woo Hyun Shim^2,6, Dong-Hou Kim³, Youngsup Song⁴and Seung-Yong Yoon^1,3,7

¹ADEL Institute of Science & Technology (AIST), ADEL, Inc., Seoul, South Korea.

²Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

³Department of Brain Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

⁴Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

⁵Department of Cell and Genetic Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

⁶Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

⁷Stem Cell Immunomodulation Research Center (SCIRC), University of Ulsan College of Medicine, Seoul, South Korea.

⁸These authors contributed equally: Ji-Seon Park, Hwon Heo.

Corresponding authors : Correspondence to Youngsup Song or Seung-Yong Yoon.

Abstract

Social hierarchy has a profound impact on social behavior, reward processing, and mental health. Moreover, lower social rank can lead to chronic stress and often more serious problems such as bullying victims of abuse, suicide, or attack to society. However, its underlying mechanisms, particularly their association with glial factors, are largely unknown. In this study, we report that astrocyte-derived amphiregulin plays a critical role in the determination of hierarchical ranks. We found that astrocytes-secreted amphiregulin is directly regulated by cAMP response element-binding (CREB)-regulated transcription coactivator 3 (CRTC3) and CREB. Mice with systemic and astrocyte-specific CRTC3 deficiency exhibited a lower social rank with reduced functional connectivity between the prefrontal cortex, a major social hierarchy center, and the parietal cortex. However, this effect was reversed by astrocyte-specific induction of amphiregulin expression, and the epidermal growth factor domain was critical for this action of amphiregulin. These results provide evidence of the involvement of novel glial factors in the regulation of social dominance and may shed light on the clinical application of amphiregulin in the treatment of various psychiatric disorders.

논문정보

형식Research article
게재일2023년 09월 (BRIC 등록일 2023-09-25)
연구진국내 연구진
분야 의약학 > 신경의학

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