Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, United States.
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States.
Elife. 2020 Dec 1;9:e58765. doi: 10.7554/eLife.58765.
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 and , in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBα, and deletion of REV-ERBα causes increased expression of transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBα 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-ERBα expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERBα deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERBα axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.
生物钟调节大脑健康的各个方面，包括小胶质细胞和星形胶质细胞的激活。在这里，我们报告说，在小鼠中敲除主时钟蛋白 BMAL1 会强烈增加海马体中补体基因的表达，包括 和 。BMAL1 调节转录抑制因子 REV-ERBα 的表达，而 REV-ERBα 的缺失会导致神经元和星形胶质细胞中 的转录本表达增加，以及主要在星形胶质细胞中 C3 蛋白的表达增加。REV-ERBα 的缺失会增加小胶质细胞对突触的吞噬作用，并导致海马体 CA3 区的突触丢失。最后，我们观察到小胶质细胞吞噬突触的程度存在昼夜变化，与 REV-ERBα 的表达呈相反相位。这种小胶质细胞吞噬突触的每日变化被全局 REV-ERBα 缺失所消除，这导致持续升高的突触吞噬作用。这项工作揭示了 BMAL1-REV-ERBα 轴作为大脑中补体表达和突触吞噬的调节剂，将生物钟蛋白与突触调节联系起来。
