Microglia Loss Contributes to the Development of Major Depression Induced by Different Types of Chronic Stresses

Recently, the loss and dystrophy of hippocampal microglia induced by chronic unpredictable stress (CUS) has been reported to mediate the development of major depression in mice whose microglial cells were labeled with enhanced green fluorescent protein-conjuncted-CX3C receptor type 1. However, whether this happens in endogenous microglia with no genetic intervention remains unclear. Here, we addressed this issue in mice treated with different types of chronic stresses, including the CUS, chronic restraint stress (CRS) and chronic social defeat stress (CSDS). Results showed that the cellular numbers, process lengths, soma areas and activation markers of endogenous hippocampal but not cortical microglia, were markedly reduced by CUS, CRS and CSDS treatment. Administration of mice with two classical stimulators of microglia, lipopolysaccharide (LPS) or macrophage colony-stimulating factor (M-CSF), reversed the CUS-, CRS- and CSDS-induced reductions in endogenous hippocampal microglial numbers, and also improved the CUS-, CRS- or CSDS-induced behavioral abnormalities, including the increases in the immobile time in the forced swimming test and tail suspension test, the inhibition of sucrose preference, and the decrease in the time spent in the center of open field. Furthermore, inhibition of the initial activation of hippocampal microglia by minocycline pretreatment also reversed the reduction in hippocampal microglial numbers as well as the behavioral abnormalities induced by CUS, CRS and CSDS treatment. These results provide compelling evidences to show that different types of chronic stresses can trigger the loss of endogenous hippocampal microglia and restoration of microglial numbers may have therapeutic values in major depression.