Hope Keenan T, Hawes Isobel A, Moca Eric N, Bonci Antonello, De Biase Lindsay M
Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
Eur J Neurosci. 2020 Oct;52(7):3689-3709. doi: 10.1111/ejn.14740. Epub 2020 May 11.
Microglia play critical roles during CNS development and undergo dramatic changes in tissue distribution, morphology, and gene expression as they transition from embryonic to neonatal to adult microglial phenotypes. Despite the magnitude of these phenotypic shifts, little is known about the time course and dynamics of these transitions and whether they vary across brain regions. Here, we define the time course of microglial maturation in key regions of the basal ganglia in mice, where significant regional differences in microglial phenotype are present in adults. We found that microglial density peaks in the ventral tegmental area (VTA) and nucleus accumbens (NAc) during the third postnatal week, driven by a burst of microglial proliferation. Microglial abundance is then refined to adult levels through a combination of tissue expansion and microglial programmed cell death. This overproduction and refinement of microglia was significantly more pronounced in the NAc than in the VTA and was accompanied by a sharp peak in NAc microglial lysosome abundance in the third postnatal week. Collectively, these data identify a key developmental window when elevated microglial density in discrete basal ganglia nuclei may support circuit refinement and could increase susceptibility to inflammatory insults.
小胶质细胞在中枢神经系统发育过程中发挥着关键作用，并且在从胚胎期小胶质细胞表型过渡到新生期再到成年期小胶质细胞表型的过程中，其在组织分布、形态和基因表达方面会发生显著变化。尽管这些表型转变幅度很大，但对于这些转变的时间进程和动态变化以及它们是否在不同脑区存在差异，我们却知之甚少。在此，我们确定了小鼠基底神经节关键区域中小胶质细胞成熟的时间进程，在成年小鼠中这些区域的小胶质细胞表型存在显著的区域差异。我们发现，在出生后第三周，腹侧被盖区（VTA）和伏隔核（NAc）中的小胶质细胞密度达到峰值，这是由小胶质细胞的一阵增殖驱动的。随后，通过组织扩张和小胶质细胞程序性细胞死亡的共同作用，小胶质细胞丰度被调整至成年水平。小胶质细胞的这种过度产生和调整在NAc中比在VTA中更为明显，并且在出生后第三周，NAc小胶质细胞溶酶体丰度出现了一个尖峰。总体而言，这些数据确定了一个关键的发育窗口期，在此期间离散的基底神经节核中小胶质细胞密度升高可能支持神经回路的精细化，并可能增加对炎症损伤的易感性。
