43. The role of dynamic microglial alterations in stress-induced depression and suppressed neurogenesis

Studies on the biological basis of major depression usually focus on abnormalities in neuronal functions. Glia cells, particularly astrocytes, have also been implicated in the pathophysiology of depression, however the role of microglia in this disease is still elusive. To elucidate the involvement of microglia in depression we examined the role of dynamic alterations in microglia activation status on the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2–3 days) of stress-induced microglial activation (reflected by proliferation, assumption of activated morphology and mRNA expression of activation markers), some microglia underwent apoptosis (reflected by activated caspase-3 and TUNEL staining), leading to reductions in their numbers within the hippocampus (but not in other brain regions) following 5-weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. The effects of CUS on microglia were blocked by chronic treatment with the tricyclic antidepressant drug imipramine. Furthermore, blockade of the initial stress-induced microglia activation by the microglial inhibitor minocycline or by transgenic interleukin-1 receptor antagonist over-expression rescued the subsequent microglia apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. These findings provide direct causal evidence that disturbances in microglial functioning have an etiological role in chronic stress-induced depression.