Socodato, RenatoAlmeida, Tiago O.Portugal, Camila C.Santos, Evelyn C.S.Tedim-Moreira, JoanaFerreira, João GalvãoCanedo, TeresaBaptista, Filipa I.Magalhães, AnaAmbrósio, António F.Brakebusch, CordRubinstein, BorisMoreira, Irina S.Summavielle, TeresaPinto, Inês MendesRelvas, João B.2024-03-052024-03-052023-12-26Socodato, R., Almeida, T. O., Portugal, C. C., Santos, E. C. S., Tedim-Moreira, J., Galvão-Ferreira, J., Canedo, T., Baptista, F. I., Magalhães, A., Ambrósio, A. F., Brakebusch, C., Rubinstein, B., Moreira, I. S., Summavielle, T., Pinto, I. M., & Relvas, J. B. (2023). Microglial Rac1 is essential for experience-dependent brain plasticity and cognitive performance. Cell Reports, 42(12), 113447. https://doi.org/10.1016/j.celrep.2023.113447http://hdl.handle.net/10400.22/25126Microglia, the largest population of brain immune cells, continuously interact with synapses to maintain brain homeostasis. In this study, we use conditional cell-specific gene targeting in mice with multi-omics approaches and demonstrate that the RhoGTPase Rac1 is an essential requirement for microglia to sense and interpret the brain microenvironment. This is crucial for microglia-synapse crosstalk that drives experience-dependent plasticity, a fundamental brain property impaired in several neuropsychiatric disorders. Phosphoproteomics profiling detects a large modulation of RhoGTPase signaling, predominantly of Rac1, in microglia of mice exposed to an environmental enrichment protocol known to induce experience-dependent brain plasticity and cognitive performance. Ablation of microglial Rac1 affects pathways involved in microglia-synapse communication, disrupts experience-dependent synaptic remodeling, and blocks the gains in learning, memory, and sociability induced by environmental enrichment. Our results reveal microglial Rac1 as a central regulator of pathways involved in the microglia-synapse crosstalk required for experience-dependent synaptic plasticity and cognitive performance.engMicroglia Rac1RhoGTPasesSynaptic plasticityGlia-neuron interactionsProteomicsRNA seqEnvironmental enrichmentCognitionjournal article10.1016/j.celrep.2023.1134472211-1247