Microglial deletion induces despair-like behavior associated with astrogliosis

Microglia, the brain's resident immune cells, are increasingly recognized as key regulators of brain physiology and behavior. However, their specific role in affective states remains controversial, with studies reporting conflicting depression-like outcomes following their removal. Using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 in adult mice of both sexes, we found that microglial deletion selectively induced despair-like behavior (increased immobility in the forced swim test and the tail suspension test) in either sex, without affecting locomotion, anxiety, sociability, anhedonia, or cognition. This effect was accompanied by reactive astrogliosis in the medial prefrontal cortex (mPFC). Unexpectedly, microglial deletion induced a predominant A2-like astrocyte reactivity. Notably, both the despair-like and A2-like phenotypes resolved upon microglia repopulation. Critically, pharmacological inhibition of these hyperactive mPFC astrocytes with fluorocitrate reversed the despair-like phenotype, indicating that microglial loss triggers maladaptive astrocyte reactivity that drives behavioral despair. Our results reveal an essential role for microglia in maintaining emotional homeostasis, possibly through interaction with astrocytes.