Astrocytic ALKBH5 in Stress Response Contributes to Depressive-like Behaviors in Mice

Overview

Journal Nat Commun

Specialty Biology

Date 2024 May 21

PMID 38773146

Authors

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

Xiong Cao

Affiliations

Soon will be listed here.

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 Ca 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.

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