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Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice

Author

Listed:
  • Fang Guo

    (Southern Medical University)

  • Jun Fan

    (Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health)

  • Jin-Ming Liu

    (Southern Medical University)

  • Peng-Li Kong

    (Southern Medical University)

  • Jing Ren

    (Southern Medical University)

  • Jia-Wen Mo

    (Southern Medical University)

  • Cheng-Lin Lu

    (Southern Medical University)

  • Qiu-Ling Zhong

    (Southern Medical University)

  • Liang-Yu Chen

    (Southern Medical University)

  • Hao-Tian Jiang

    (Southern Medical University)

  • Canyuan Zhang

    (Southern Medical University)

  • You-Lu Wen

    (South China Normal University)

  • Ting-Ting Gu

    (South China Normal University)

  • Shu-Ji Li

    (Southern Medical University)

  • Ying-Ying Fang

    (Southern Medical University)

  • Bing-Xing Pan

    (Nanchang University)

  • Tian-Ming Gao

    (Southern Medical University)

  • Xiong Cao

    (Southern Medical University
    Southern Medical University Guangzhou
    Southern Medical University)

Abstract

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients’ blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

Suggested Citation

  • Fang Guo & Jun Fan & Jin-Ming Liu & Peng-Li Kong & Jing Ren & Jia-Wen Mo & Cheng-Lin Lu & Qiu-Ling Zhong & Liang-Yu Chen & Hao-Tian Jiang & Canyuan Zhang & You-Lu Wen & Ting-Ting Gu & Shu-Ji Li & Ying, 2024. "Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48730-2
    DOI: 10.1038/s41467-024-48730-2
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