Microglial Phagocytosis of Newborn Cells Is Induced by Endocannabinoids and Sculpts Sex Differences in Juvenile Rat Social Play

Brain sex differences are established developmentally and generate enduring changes in circuitry and behavior. Steroid-mediated masculinization of the rat amygdala during perinatal development produces higher levels of juvenile rough-and-tumble play by males. This sex difference in social play is highly conserved across mammals, yet the mechanisms by which it is established are unknown. Here, we report that androgen-induced increases in endocannabinoid tone promote microglia phagocytosis during a critical period of amygdala development. Phagocytic microglia engulf more viable newborn cells in males; in females, less phagocytosis allows more astrocytes to survive to the juvenile age. Blocking complement-dependent phagocytosis in males increases astrocyte survival and prevents masculinization of play. Moreover, increased astrocyte density in the juvenile amygdala reduces neuronal excitation during play. These findings highlight novel mechanisms of brain development whereby endocannabinoids induce microglia phagocytosis to regulate newborn astrocyte number and shape the sexual differentiation of social circuitry and behavior. [Display omitted] •Microglia are more phagocytic in the male amygdala during neonatal development•Androgen-induced endocannabinoids increase phagocytosis in males•Microglia engulf viable newborn astrocytes in a complement-dependent manner•Developmental phagocytosis produces a sex difference in juvenile social play VanRyzin et al. demonstrate that microglia in the developing amygdala engulf and kill otherwise viable newborn astrocytes, establishing sex differences in social circuits. This process, which depends on gonadal hormones and endocannabinoid signaling, promotes juvenile play by males.