Genetic ablation of RhoA in adult microglia causes synapse and neuronal loss

Microglia, the resident myeloid cells of the central nervous system parenchyma, are critical for brain functioning in health and disease. Here, using tissue-specific conditional gene targeting in mice, we show an essential role for the small GTPase RhoA in regulating microglia homeostasis and brain pathology. We reveal that in the absence of brain disease or any insult, the microglia-specific ablation of RhoA disrupted the quiescence of adult microglia leading to their activation, which culminated in astrogliosis, inflammation, synapse and neuronal loss, impairment of long-term potentiation and memory deficts. RhoA exerted its microglial homeostatic functions by sustaining C-terminal Src kinase (Csk) negative regulation of Src tyrosine kinase activity. Accordingly, inhibition of Src with a clinically-relevant inhibior prevented microglia deregulation and synapse loss restoring the memory performance of mice with microglia-specific ablation of RhoA. Overall, loss of RhoA in adult brain microglia leads to a neurodegenerative-like pathology mediated by deregulated microglial activation.