Dopaminergic signaling regulates microglial surveillance and adolescent plasticity in the mouse frontal cortex

Abstract Adolescence is a sensitive period for frontal cortical development and cognitive maturation, marked by heightened structural plasticity in the dopaminergic (DA) mesofrontal circuit. However, the cellular and molecular mechanisms underlying this plasticity remain unclear. Here, we show that microglia, the brain’s innate immune cells, are highly responsive to mesofrontal DA signaling during adolescence. Longitudinal in vivo two-photon imaging in mice reveals that frontal cortical microglia increase their surveillance of the parenchyma and DA axonal boutons following rewarding experiences or optogenetic stimulation of DA axons. Microglial contacts with DA axons consistently precede bouton formation, and microglia-bouton interactions are regulated by D1- and D2-type DA receptors in adolescence and adulthood. Furthermore, microglial purinergic receptor P2RY12 signaling is necessary for enhanced microglial surveillance and DA bouton formation during adolescence. These results uncover bidirectional interactions between DA signaling and microglial surveillance that drive adolescent frontal plasticity and identify potential targets for restoring plasticity in adulthood.