LAUSR

Summary Microglia seed the embryonic neuro‐epithelium, expand and actively sculpt neuronal circuits in the developing central nervous system, but eventually adopt relative quiescence and ramified morphology in the adult. Here, we probed the impact of post‐transcriptional control by microRNAs (miRNAs) on microglial performance during development and adulthood by generating mice lacking microglial Dicer expression at these distinct stages. Conditional Dicer ablation in adult microglia revealed that miRNAs were required to limit microglial responses to challenge. After peripheral endotoxin exposure, Dicer‐deficient microglia expressed more pro‐inflammatory cytokines than wild‐type microglia and thereby compromised hippocampal neuronal functions. In contrast, prenatal Dicer ablation resulted in spontaneous microglia activation and revealed a role for Dicer in DNA repair and preservation of genome integrity. Accordingly, Dicer deficiency rendered otherwise radio‐resistant microglia sensitive to gamma irradiation. Collectively, the differential impact of the Dicer ablation on microglia of the developing and adult brain highlights the changes these cells undergo with time. Graphical Abstract Figure. No Caption available. HighlightsmiRNAs curb activation of adult microglia after challengeAdult microglia hyper‐activation impairs hippocampal neuronal functionsDicer‐deficient microglia proliferating in developing brain accumulate DNA damageMicroglia of the developing and adult brain are functionally distinct &NA; Microglia of developing and adult brain differ in activation state and function. Here, Varol and colleagues ablated microglial Dicer expression at distinct times. Adult microglia tolerated the perturbation but became hyper‐responsive to challenge compromising hippocampus functions. Dicer and microRNA absence during development caused spontaneous microglia activation and impaired genome integrity.