Microglia Monitor and Protect Neuronal Function Via Specialized Somatic Purinergic Junctions in an Activity-Dependent Manner

Microglia are the main immune cells in the brain with emerging roles in neurological diseases, while the mechanisms underlying microglia-neuron communication remain elusive. Here we identify a novel site of interaction between neuronal cell bodies and microglial processes in the mouse and human brain. Somatic microglia-neuron junctions have specialized molecular composition and unique nanoarchitecture optimized for purinergic signaling. Activity of neuronal mitochondria is linked with microglial junction formation, which is rapidly induced in response to neuronal activation and blocked by inhibition of P2Y12 receptors (P2Y12R). Brain injury-induced changes at somatic junctions trigger protective microglial responses, while blockade of P2Y12R signaling augments neuronal calcium load and defects in functional connectivity, leading to increased brain injury. Collectively, our results suggest that microglial processes recruited to these morpho-functional communication sites are in ideal position to monitor and protect neuronal functions via mitochondrion- and P2Y12R-dependent signaling pathways in both the healthy and injured brain.