Complement and microglia activation mediate stress-induced synapse loss in layer 2/3 of the medial prefrontal cortex in male mice
Haven Tillmon, Breeanne M. Soteros, Liang Shen, Qifei Cong, Mackenna Wollet, Julianne General, Hanna Chin, John Beichen Lee, Flavia Carreño, David A. Morilak, Jun Hee Kim, Gek-Ming Sia
Abstract
Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the medial prefrontal cortex (mPFC) in male mice. Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (Apoehigh) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the Apoehigh microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases. Synapse loss is central to the pathogenesis of stress-related disorders. Here, the authors show that targeted synapse removal by microglia and complement during stress contributes to the effects of stress on behavior.