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

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.

Glucocorticoid Receptor-Dependent Astrocytes Mediate Stress Vulnerability.

BACKGROUND: Major depressive disorder is a devastating psychiatric illness that affects approximately 17% of the population worldwide. Astrocyte dysfunction has been implicated in its pathophysiology. Traumatic experiences and stress contribute to the onset of major depressive disorder, but how astrocytes respond to stress is poorly understood. METHODS: Using Western blotting analysis, we identified that stress vulnerability was associated with reduced astrocytic glucocorticoid receptor (GR) expression in mouse models of depression. We further investigated the functions of astrocytic GRs in regulating depression and the underlying mechanisms by using a combination of behavioral studies, fiber photometry, biochemical experiments, and RNA sequencing methods. RESULTS: GRs in astrocytes were more sensitive to stress than those in neurons. GR absence in astrocytes induced depressive-like behaviors, whereas restoring astrocytic GR expression in the medial prefrontal cortex prevented the depressive-like phenotype. Furthermore, we found that GRs in the medial prefrontal cortex affected astrocytic Ca2+ activity and dynamic ATP (adenosine 5'-triphosphate) release in response to stress. RNA sequencing of astrocytes isolated from GR deletion mice identified the PI3K-Akt (phosphoinositide 3-kinase-Akt) signaling pathway, which was required for astrocytic GR-mediated ATP release. CONCLUSIONS: These findings reveal that astrocytic GRs play an important role in stress response and that reduced astrocytic GR expression in the stressed subject decreases ATP release to mediate stress vulnerability.