P2Y12 Receptor Function Governs Microglial Surveillance and Cell–Cell Interactions in the Cerebral Cortex

ABSTRACT Microglia are unique damage sensors of the central nervous system, and their homeostatic roles are increasingly recognized. Purinergic signaling through the P2Y12 receptor (P2Y12R) is indispensable for directed process movement of microglia in response to danger‐related ATP release. P2Y12R has also been shown to modulate microglial communication with neurovascular elements in the brain and to profoundly influence outcomes in experimental models of brain injury. However, the exact role of P2Y12R in shaping microglial phenotypes and interactions under physiological conditions remains unresolved due to disagreements between ex vivo and in vivo observations. Using in vivo 3D two‐photon imaging and high‐resolution anatomy we show that P2Y12Rs are essential regulators of microglial physiology, fundamentally shaping homeostatic microglial surveillance activity and direct contacts with other cell types. Genetic deletion or acute pharmacological blockade of P2Y12R function leads to altered surveillance activity, microglial morphology and P2Y12R nanoclustering, resulting in changes of direct microglial contacts with neuronal cell bodies, smooth muscle‐bearing blood vessels and oligodendrocyte processes in the somatosensory cortex of mice. Furthermore, molecular anatomy of P2Y12R expression shows correlation with disease severity and altered microglia–neuron interactions in human epilepsy. Thus, our results identify P2Y12Rs as major participants in microglial physiology whose dysfunction could impact defined cell–cell interactions in different neurological states.