Stress induces behavioral abnormalities by increasing expression of phagocytic receptor MERTK in astrocytes to promote synapse phagocytosis

Early life stress such as childhood abues and childhood neglect has been frequently implicated in evoking mental disorders later in life. However, it is not well understood what is the underlying mechanism between early life stress and mental disorders. Our in vitro, in vivo and brain organoid experiments revealed that stress hormones increase Mertk expression in astrocytes through glucocorticoid receptor (GR). Furthermore, early life stress (ESD) exposure significantly incrased astrocyte-mediated synapse phagocytosis via GR/MERTK pathway in various brain regions including somatosensory cortex and orbitofrontal cortex. In those brain regions, the excitatory postsynaptic density was remarkably decreased with an increase in astrocytic phagocytosis of excitatory postsynapses. Importantly, ablating GR or MERTK in astrocytes prevented ESD-induced loss of excitatory snapses, abnormal neural activities and behavioral deficits. Taken together, this study revelas a new role of astrocytic GR/MERTK pathway in evoking stress-induced abnormal behaviors in mice, suggesting astrocytic GR/MERTK signaling could be a potential therapeutic target for stress-induced mental disorders. To investigate the gene expression changes in astrocytes in control and astrocyte-specific GR knock-out mice (AGR cKO) after early life stress (ESD), we have designed four different groups (control Cre- mice: Cre- control, Cre- mice exposed to ESD: Cre- ESD, control AGR cKO mice: AGR cKO control, AGR cKO mice exposed to ESD: AGR cKO ESD). All four groups were injected 4-hydroxytamoxifen (4-OHT) from P5 to P7. The ESD group pups were separated from their dam for three hours a day from P1 to P14. Astrocytes were prufied from the cortices from four different groups at postnatal day 14 (P14) by utilizing immunopanning methods and Miltenyi Biotec beads.