Major depressive disorder is a recurring neuropsychiatric illness that affects up to 17% of the population and causes significant social and economic burden. Clinical and basic research show that depressive symptoms stem from neuroplasticity deficits in the medial prefrontal cortex (mPFC) and hippocampus (HPC). Moreover, recent studies indicate that microglia, resident immune cells in the brain, play an important role in neuroplasticity. The primary objective of the current studies is to determine the role of microglia in neuroplasticity deficits and development of depressive-like behavior in male and female mice exposed to 14days of chronic unpredictable stress (CUS). Initial immunohistology showed that microglia in male mice displayed an activated morphological phenotype in the mPFC, but appeared dystrophic in the HPC after CUS. In contrast, female mice showed no morphological changes in the mPFC or HPC. Consistent with these results, mRNA levels of colony stimulating factor-1 (CSF1) were increased in the mPFC, but reduced in the HPC after CUS. Furthermore, CUS increased CSF1 receptor expression in enriched microglia from male mice. To further examine neuron-microglia interactions transgenic Thy-1 (GFP) mice were used. Immunohistology analyses showed that CUS increased phagocytosis of pyramidal neuron elements in the mPFC of male mice. These findings suggest that stress-induced alterations in neuron-derived signals lead to microglia dysfunction and may contribute to microglia-mediated dendritic remodeling of pyramidal neurons in the mPFC.