Browsing by Author "Baptista, Filipa I."
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- Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegenerationPublication . Socodato, Renato; Portugal, Camila C.; Canedo, Teresa; Rodrigues, Artur; Almeida, Tiago O.; Henriques, Joana F.; Vaz, Sandra H.; Magalhães, João; Silva, Cátia M.; Baptista, Filipa I.; Alves, Renata L.; Coelho-Santos, Vanessa; Silva, Ana Paula; Paes-de-Carvalho, Roberto; Magalhães, Ana; Brakebusch, Cord; Sebastião, Ana M.; Summavielle, Teresa; Ambrósio, António F.; Relvas, João B.Nervous tissue homeostasis requires the regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation, producing a neurological phenotype (including synapse and neuron loss, impairment of long-term potentiation [LTP], formation of β-amyloid plaques, and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated tumor necrosis factor (TNF) production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also find that the Rhoa/Src signaling pathway is disrupted in microglia of the APP/PS1 mouse model of Alzheimer disease and that low doses of Aβ oligomers trigger microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing Rho GTPase signaling in microglia can directly cause neurodegeneration.
- Microglial Rac1 is essential for experience-dependent brain plasticity and cognitive performancePublication . Socodato, Renato; Almeida, Tiago O.; Portugal, Camila C.; Santos, Evelyn C.S.; Tedim-Moreira, Joana; Ferreira, João Galvão; Canedo, Teresa; Baptista, Filipa I.; Magalhães, Ana; Ambrósio, António F.; Brakebusch, Cord; Rubinstein, Boris; Moreira, Irina S.; Summavielle, Teresa; Pinto, Inês Mendes; Relvas, João B.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.