7. The role of microglia in stress-induced depression

Abstract

Despite impressive progress in understanding the molecular, cellular and circuit-level correlates of major depression, the biological mechanisms that causally underlie this disorder are still unclear, possibly due to excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We found that following an initial period (2–3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline, imipramine or by transgenic interleukin-1 receptor antagonist over-expression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depression and suppressed neurogenesis. Treatment of CUS-exposed mice with LPS (endotoxin), M-CSF or GM-CSF, which all stimulated hippocampal microglial proliferation, reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal anti-depressive effects in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.