Dynamic changes in hippocampal microglia contribute to depressive-like behavior induced by early social isolation

Depression triggered by early-life stress has begun to attract wide attention due to its severe symptoms and poor treatment outcomes. However, the pathophysiological mechanism for this type of depression remains unclear. Recently, we and Others reported that different types of chronic stress induce a significant loss of hippocampal microglia, which is mediated by an initial activation of these microglia. Since early-life stress also promotes microglial activation, we investigated the dynamic changes in hippocampal microglia in mice suffering from depression induced by early social isolation (ESI). Results showed that 8 days of ESI induced depressive-like behaviors in a tail suspension test, forced swim test, sucrose preference test, and open field test, and it also induced a loss and dystrophy of hippocampal microglia. We found that this ESI-induced loss of hippocampal microglia was mediated by both microglial activation and Apoptosis. This was demonstrated by the following results: (i) 1 day of ESI induced an obvious activation of hippocampal microglia followed by their Apoptosis, and (ii) the blockade of the initial activation of hippocampal microglia by minocycline pretreatment suppressed the ESI-induced Apoptosis and loss as well as ESI-induced depressive-like behavior. Lipopolysaccharide (LPS) and macrophage colony-stimulating factor (M-CSF), two activators of microglia, almost completely reversed ESI-induced depressive-like behavior by promoting microglial proliferation in the hippocampus. These results reveal an etiological role of hippocampal microglial loss in ESI-induced depression and demonstrate that the restoration of microglial homeostasis in the hippocampus may serve as a therapeutic strategy for depression induced by early-life stress.