Microglial Rac1 is essential for experience-dependent brain plasticity and cognitive performance
Renato Socodato,
Tiago O. Almeida,
Camila C. Portugal,
Evelyn C.S. Santos,
Joana Tedim-Moreira,
João Galvão-Ferreira,
Teresa Canedo,
Filipa I. Baptista,
Ana Magalhães,
António F. Ambrósio,
Cord Brakebusch,
Boris Rubinstein,
Irina S. Moreira,
Teresa Summavielle,
Inês Mendes Pinto,
João B. Relvas
Affiliations
Renato Socodato
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal; Corresponding author
Tiago O. Almeida
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal; ICBAS - School of Medicine and Biomedical Sciences, Porto, Portugal
Camila C. Portugal
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal
Evelyn C.S. Santos
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal; Department of Biomedicine, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
Joana Tedim-Moreira
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal; Department of Biomedicine, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
João Galvão-Ferreira
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal; Department of Biomedicine, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
Teresa Canedo
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal
Filipa I. Baptista
Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra Institute for Clinical and Biomedical Research (iCBR), and Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
Ana Magalhães
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal
António F. Ambrósio
Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra Institute for Clinical and Biomedical Research (iCBR), and Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
Cord Brakebusch
Molecular Pathology Section, BRIC, Københavns Biocenter, Copenhagen, Denmark
Boris Rubinstein
Stowers Institute for Medical Research, Kansas City, MO, USA
Irina S. Moreira
Department of Life Sciences, Center for Innovative Biomedicine and Biotechnology (CIBB) and CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Teresa Summavielle
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal; ESS.PP, Escola Superior de Saúde do Politécnico do Porto, Porto, Portugal
Inês Mendes Pinto
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal; Department of Biomedicine, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
João B. Relvas
Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal; Department of Biomedicine, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal; Corresponding author
Summary: 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.
