Percorrer por autor "Santos, Evelyn C. S."
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- Microglial RAC1 drives experience-dependent brain plasticityPublication . Almeida, Tiago O.; Portugal, Camila C.; Santos, Evelyn C. S.; Moreira, Joana Tedim; Ferreira, João Galvão; Canedo, Teresa; Magalhães, Ana; Summavielle, Teresa; Summavielle, TeresaMicroglia, the immune defenders of the brain, continuously extend and retract their processes to sense and decipher their local environment. This includes interactions with synapses to maintain brain homeostasis. To do this, microglia rely on the actin cytoskeleton and subsequent intracellular signaling, which is adapted in response to external signals released by cells undergoing intense synaptic activity. Thus, proteins that regulate actin cytoskeleton dynamics, intracellular trafficking, and integration of extracellular signaling, such as RhoA, Rac1 and Cdc42 from the Rho GTPase family, are good candidates to govern microglial sensing capacity and homeostasis. In this study, using conditional cellspecific gene targeting in mice combined with multi-omics approaches, immunofluorescence, and behavioral tests we aimed to identify the roles of Rho GTPase Rac1 in microglia homeostasis. We demonstrate that the Rho GTPase Rac1 is essential for microglia to sense and interpret their local microenvironment. This impacts the microglia-synapse crosstalk that is required for experiencedependent plasticity, a fundamental brain property impaired in several neuropsychiatric disorders. Furthermore, phosphoproteomics profiling of microglia isolated from mice exposed to an environmental enrichment protocol (known to induce experience-dependent synaptic plasticity and cognitive performance) detects a large modulation of Rho GTPase signaling, predominantly of Rac1. Additionally, our results show that environmental enrichment likely requires tight regulation of Rho GTPase-dependent pathways. Ablation of microglial Rac1 affected pathways involved in microglia-synapse communication, disrupted experience-dependent synaptic remodeling and blocked the gains in learning, memory, and sociability induced by environmental enrichment. Overall, our results place microglial Rac1 as a central regulator of pathways involved in the microglia-synapse crosstalk required for experience-dependent synaptic plasticity and cognitive performance, suggesting that modulation of Rho GTPase signaling in microglia might be a useful strategy to boost neuroplasticity in health and disease.
- Microglial Rac1 is essential for microglia-synapse crosstalk and cognitive performancePublication . Almeida, Tiago O.; Socodato, Renato; Portugal, Camila C.; Santos, Evelyn C. S.; Moreira, Joana Tedim; Ferreira, João Galvão; Canedo, Teresa; Magalhães, Ana; Summavielle, Teresa; Relvas, João B.; Summavielle, TeresaMicroglia, the main immune defenders of the brain, rapidly detect and react to stimuli due to constant extension andretraction of their processes. When engaged by external cues, that can be either inflammatory or products resulting from synaptic activity, microglia dramatically change their morphology and initiate a response to reestablish brain homeostasis. Additionally, microglia can also regulate and sustain synaptic activity by secreting a plethora of factors. While some of these factors are already described, there is still much to understand on how exactly microglia-secreted factors modulate synaptic function. Rac1, a well-known member of the Rho GTPase family, is a critical regulator of actin cytoskeleton dynamics and reorganization. Furthermore, Rac1 is a component of NADPH oxidase complex, a key element for phagocytic cup formation and it also regulates NF-κB pathway activation. In the central nervous system (CNS), Rac1 is involved in axon guidance and growth, but it is also linked with Alzheimer´s disease,since it regulates the expression of amyloid precursor protein in hippocampal neurons. Although extensively studied in other cell types in and outside of the CNS, there is a profound knowledge gap on how Rac1 regulates microglia function in homeostasis and in response to external stimuli. Combining cell-specific conditional gene ablation, RNAseq, flow cytometry, immunofluorescence, proteomics and phosphoproteomics, FRET live cell imaging and mouse behavior, we aimed at describing for the first time Rac1 roles in microglial function. We observed that microglia specific Rac1 ablation impaired the capacity of microglia to sense and respond to changes in their local environment. To promote changes on the brain environment, we performed a protocol of environmental enrichment (EE), mimicking currently used therapeutic approaches for enhancing brain plasticity in patients with brain disorders. EE had a profound impact on the microglial phosphoproteomic landscape, showing a strong effect on Rho GTPase signaling. Interestingly, we showed that Rac1 signaling was the most significantly altered pathway, followed by Cdc42 and RhoA signaling, allowing us to define a hierarchy between them. Besides, EE led to an overall improvement of cognitive performance. Strikingly, ablating Rac1 from microglia completely prevented this EE-dependent cognitive enhancement and disrupted microglia-synapse crosstalk, ultimately impacting the synaptic proteomic and phosphoproteomic profiles of these mice. Overall, this is a first step into understanding how Rac1 mediates microglial responses to their local environment. This places Rac1 as anessential target for further studies and reinforces the importance of Rho GTPases signaling for adult microglial function.