Astrocytes-induced neuronal inhibition contributes to depressive-like behaviors during chronic stress

Although emerging evidence has highlighted the heterogeneities of astrocytes under physiological versus pathological conditions, little is known regarding these processes in different brain regions during stress. Thus, the present study established a mouse model of chronic social defeat stress (CSDS) and isolated astrocytes from the medial prefrontal cortex (mPFC) and hippocampus. The results revealed dramatic A1-specific (neurotoxic phenotype) astrocytic responses, depressive-like behaviors, and significant inhibition of neuronal activities in both the mPFC and hippocampus according to electrophysiological data. Subsequently, astrocytes in the mPFC and hippocampus of CSDS mice were suppressed and this reversed the astrocytic responses and rescued depressive-like behaviors. Furthermore, when astrocytes were activated in the mPFC and hippocampus in healthy mice, there was a non-specific phenotypic activation of astrocytes in the absence of depressive-like behaviors. Next, microglia were depleted and the mice subsequently performed in the CSDS model; this reduced astrocyte responses and restored depressive-like behaviors. On the other hand, when microglia were depleted but astrocytes were activated in CSDS mice, this abolished the restoration of microglia depletion-induced depressive-like behaviors. Taken together, these results indicate that neuronal inhibition by astrocytes in the mPFC and hippocampus contributed to depressive-like behaviors mediated by activated microglia. This study provides evidence regarding the interaction of microglia and astrocytes during stress and how that relationship can trigger depressive-like behaviors.