Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
J Exp Med. 2019 Oct 7;216(10):2265-2281. doi: 10.1084/jem.20182037. Epub 2019 Jul 26.
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.
小胶质细胞是大脑常驻的巨噬细胞，对大脑皮质神经元回路的形成起着至关重要的作用。然而，其在小脑的确切功能尚不清楚。本研究表明，人类和小鼠小脑小胶质细胞表达一种独特的分子程序，与大脑皮质小胶质细胞不同。小脑小胶质细胞的特征由 CSF-1R 配体 CSF-1 驱动，而不依赖于替代 CSF-1R 配体 IL-34。因此，巢蛋白细胞中 CSF-1 的耗竭导致小脑小胶质细胞严重耗竭和转录改变，而大脑皮质的小胶质细胞保持完整。引人注目的是，CSF-1 缺乏和小脑小胶质细胞改变与浦肯野细胞减少、神经元功能改变以及运动学习和社会新奇互动缺陷有关。这些发现揭示了一种新型 CSF-1-CSF-1R 信号转导介导的机制，有助于运动功能和社会行为。
