Rev-erbα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis

The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including C4b and C3, in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBa, and deletion of REV-ERBa causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBa deletion increased microglial phagocytosis of synapses and synapse loss in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis which was antiphase to REV-ERBa expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERBa deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERBa axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.