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- IL-10 and Cdc42 as critical modulators in methamphtamine-induced neuroinflammationPublication . Silva, Ana Isabel; Socodato, Renato; Pinto, Carolina; Terceiro, Ana Filipa; Canedo, Teresa; Relvas, João Bettencourt; Saraiva, Margarida; Summavielle, Teresa; Summavielle, TeresaPsychoactive substances, such as Methamphetamine (Meth), can induce complex neuroinflammatory responses that modulate the neuron-glia cross talk and strongly affect behavioral responses. Recently we have reported that Meth stimulates astrocytes to release tumor necrosis factor (TNF) and glutamate, leading to microglial activation, microgliosis and loss of risk-assessment. Here, we started by investigating the anti-inflammatory power the cytokine interleukin-10 (IL-10), resorting to astrocyte and microglia primary transfected with different FRET probes and exposed to Meth (100µM), to elucidate the mechanisms involved. Then after, we confirmed these results in vivo, by employing a transgenic mouse model that overexpresses IL-10 (pMT-10), in time-controlled manner, and administering a binge Meth dosing (4 x 5mg/kg, with 2h intervals). In vitro, our findings reveal that the presence of recombinant IL-10 (rIL-10) counteracts Meth-induced excessive glutamate release in astrocytes, which significantly reduced microglial activation. This reduction was associated with the modulation of astrocytic intracellular calcium (Ca2+) dynamics, particularly by restricting the release of Ca2+ from the endoplasmic reticulum to the cytoplasm. Furthermore, we identify the small Rho GTPase Cdc42 as a crucial intermediary in the astrocyte-to-microglia communication pathway under Meth. In vivo, we observed that IL-10 overexpressing prevented Meth-induced neuroinflammation, microgliosis and Meth-induced behavioral changes. These findings enhance our understanding of Meth-related neuroinflammatory mechanisms, suggesting IL-10 and Cdc42 as putative therapeutic targets, and strengthen the view of a neuroimmune nature for addiction.
- 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.
- The role of RAC1 in methamphtamine-induced neuroinflammationPublication . Terceiro, Ana Filipa; Canedo, Teresa; Silva, Ana Isabel; Magalhães, Ana; Relvas, João; Summavielle, Teresa; Summavielle, TeresaMethamphetamine (Meth), a powerful psychostimulant, induces detrimental neuroinflammatory responses, in the brain reward system that seem to contribute to maintenance of addictive behaviour. Yet, the mechanisms regulating these processes in microglial cells are not clear. We have previously shown that exposing WT mice to Meth (4x5 mg/kg, 2h intervals) induces microgliosis concomitant with decreased microglia cell volume and ramification. Furthermore, psychostimulants are known to induce structural plasticity mechanisms in neurons, and Rho GTPases, important regulators of the actin cytoskeleton, are involved in these responses. Here, we assessed Rho GTPases, specifically rhoA, rac1 and cdc42, activation in response to Meth in microglia. Exposing WT mice to the same pattern of Meth administration, we found an increase in the activation of rac1 in the striatum, 15 min following the last administration of Meth. To further explore these results, we then used a conditional mice model for ablation of rac1 in adult microglia (Rac1fl/fl:Cx3cr1CreER+) and exposed these mice to the same pattern of Meth administration. Rac1 ablation was sufficient to prevent Meth-induced morphological alterations in the striatum. Currently, we are assessing the role of rac1 in the behavioural response to Meth, using a locomotor sensitization test. Overall, we identified rac1 as a novel target of Meth in microglial cells. With these results, we expect to clarify if targeting Rho GTPases may contribute to improving the treatment of addictive disorders.