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

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-Ying Fang, Bing-Xing Pan, Tian-Ming Gao and Xiong Cao ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48730-2

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