Layer-specific microglia activation drives chronic stress-induced synapse loss.

Microglia play a pivotal role in mediating the neurological effects of chronic stress, and is implicated in stress-associated diseases such as depression. However, the biological states of microglia in the stressed brain remains unclear. Here, using single cell RNA sequencing of mouse cortical microglia, we identify a stress-associated microglia state marked by high expression of apolipoprotein E (ApoE). In the prefrontal cortex, ApoE high microglia are localized to layer 2/3, and are caused by stress-induced local complement activation in the upper cortical layers. In mice lacking complement component C3, chronic stress does not induce the ApoE high microglial state, and these mice are protected from stress-induced synapse loss, anhedonia, and working memory deficits. Our data show that spatially-restricted complement and microglia activation can result in regional vulnerability of synapses in brain disease, and highlight the role of immune processes in causing region-specific circuit defects that are associated with many psychiatric diseases.