Microglia are key regulators of inflammatory processes in the CNS. Microglial activity is altered in common brain diseases and changes in microglial function have major impact on outcome in experimental models of neurological disorders. However, the mechanisms through which microglia contribute to the maintenance of normal brain function and impact on common CNS disorders are not well understood. We have recently identified a novel form of microglia-neuron interaction, which is present in the majority of neurons in mouse and human brain. Somatic microglia-neuron junctions possess specialized nanoarchitecture optimized for purinergic signaling. We show that activity of neuronal mitochondria is linked with microglial junction formation, which is induced rapidly in response to neuronal activation and blocked by inhibition of P2Y12 receptors. Brain injury-induced changes at somatic junctions trigger P2Y12-dependent microglial neuroprotection, regulating neuronal calcium load and functional connectivity. Our results suggest that motile microglial processes exert fine-tuned actions to influence the functioning of neurons in the healthy and the injured brain. Understanding the mechanisms of microglia-neuron interactions is likely to help the identification of novel therapeutic targets in common neurological disorders.