Microglia remodel the synaptic signaling required for context-dependent cognitive performance

Abstract Microglial homeostatic functions are fundamental to regulate the central nervous system microenvironment. We use conditional cell-specific gene targeting, RNA-seq profiling, high-throughput proteomics, phosphoproteomics, systems biology, and animal behavior to report a critical role for the RhoGTPase Rac1 in regulating adult microglia physiology. Ablation of Rac1 in adult microglia impaired their ability to sense and interpret the brain microenvironment and affected their capacity to communicate with synapses to drive cognitive performance, both at the steady-state and during experience-dependent plasticity. Overall, our results reveal a novel and central role for Rac1 as a regulator of microglia homeostasis and a molecular driver of the microglia-synapse crosstalk required for context-dependent sociability and learning related to memory.