Microglia dysfunction caused by the loss of Rhoa disrupts neuronal physiology and leads to neurodegeneration

Abstract Nervous tissue homeostasis requires 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 causing synapse and neuron loss, impairment of long-term synaptic plasticity, deficits in recognition memory and the formation of beta-amyloid plaques. We found that Rhoa function sustains Csk negative regulation of Src activity, and that its loss elicited microglia activation via Src-mediated Tnf production, leading to excitotoxic glutamate release. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia activity and the ensuing neurological phenotype. Attesting the importance of Rhoa/Csk/Src signaling in restraining microglia activity, we found that this pathway was affected in microglia of the APP/PS1 mouse model of Alzheimer’s disease. Inhibiting Src in these mice limited microglia dysregulation, decreasing amyloid burden and synapse loss. Our results indicate that disturbing RhoGTPase signaling in microglia can directly cause neurodegeneration.