Violeta Chitu, Samuel A. Rose, Anne Schaefer, Aleksandra Wroblewska, Brian D. Brown, Ana Badimon, Lotje de Witte, Zhenyu Yue, Kazuhiko Yamamuro, Maria Casanova-Acebes, Andrew Leader, Pinar Ayata, Alessia Baccarini, Florent Ginhoux, I-li Tan, Yonit Lavin, Hortense Le Bourhis, Scott J. Russo, Veronika Kana, Christie Chang, Alexandra L. Joyner, Eric S. Sweet, Peter See, Hirofumi Morishita, Navpreet Tung, Miriam Merad, Elisa M. Nabel, E. Richard Stanley, Fiona Desland, Meghan E. Flanigan, and Marjolein A. M. Sneeboer
Microglia are a heterogeneous population whose identity and function are dictated by signals from their microenvironment. Kana et al. show CSF-1 signaling is critical for cerebellar microglial transcriptional identity and homeostasis, and that altering the CSF-1–CSF-1R axis leads to motor and behavioral defects., Microglia, the brain resident macrophages, critically shape forebrain neuronal circuits. However, their precise function in the cerebellum is unknown. Here we show that human and mouse cerebellar microglia express a unique molecular program distinct from forebrain microglia. Cerebellar microglial identity was driven by the CSF-1R ligand CSF-1, independently of the alternate CSF-1R ligand, IL-34. Accordingly, CSF-1 depletion from Nestin+ cells led to severe depletion and transcriptional alterations of cerebellar microglia, while microglia in the forebrain remained intact. Strikingly, CSF-1 deficiency and alteration of cerebellar microglia were associated with reduced Purkinje cells, altered neuronal function, and defects in motor learning and social novelty interactions. These findings reveal a novel CSF-1–CSF-1R signaling-mediated mechanism that contributes to motor function and social behavior.