Microglial Rac1 is essential for experience-dependent brain plasticity and cognitive performance
Renato Socodato, Tiago O. Almeida, Camila C. Portugal, Evelyn Cristina da Silva Santos, Joana Tedim-Moreira, João Galvão-Ferreira, Teresa Canedo, Filipa I. Baptista, Ana Magalhães, António Francisco Ambrósio, Cord Brakebusch, Boris Rubinstein, Irina S. Moreira, Teresa Summavielle, Inês Mendes Pinto, João B. Relvas
Abstract
Microglia, 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.