Eyo Ukpong B, Miner Samuel A, Weiner Joshua A, Dailey Michael E
Department of Biology, University of Iowa, Iowa City, IA 52242, United States.
Department of Biology, University of Iowa, Iowa City, IA 52242, United States.
Brain Behav Immun. 2016 Jul;55:49-59. doi: 10.1016/j.bbi.2015.11.009. Epub 2015 Nov 11.
During CNS development, microglia transform from highly mobile amoeboid-like cells to primitive ramified forms and, finally, to highly branched but relatively stationary cells in maturity. The factors that control developmental changes in microglia are largely unknown. Because microglia detect and clear apoptotic cells, developmental changes in microglia may be controlled by neuronal apoptosis. Here, we assessed the extent to which microglial cell density, morphology, motility, and migration are regulated by developmental apoptosis, focusing on the first postnatal week in the mouse hippocampus when the density of apoptotic bodies peaks at postnatal day 4 and declines sharply thereafter. Analysis of microglial form and distribution in situ over the first postnatal week showed that, although there was little change in the number of primary microglial branches, microglial cell density increased significantly, and microglia were often seen near or engulfing apoptotic bodies. Time-lapse imaging in hippocampal slices harvested at different times over the first postnatal week showed differences in microglial motility and migration that correlated with the density of apoptotic bodies. The extent to which these changes in microglia are driven by developmental neuronal apoptosis was assessed in tissues from BAX null mice lacking apoptosis. We found that apoptosis can lead to local microglial accumulation near apoptotic neurons in the pyramidal cell body layer but, unexpectedly, loss of apoptosis did not alter overall microglial cell density in vivo or microglial motility and migration in ex vivo tissue slices. These results demonstrate that developmental changes in microglial form, distribution, motility, and migration occur essentially normally in the absence of developmental apoptosis, indicating that factors other than neuronal apoptosis regulate these features of microglial development.
在中枢神经系统发育过程中,小胶质细胞从高度可移动的阿米巴样细胞转变为原始的分支状形态,最终在成熟时转变为高度分支但相对静止的细胞。控制小胶质细胞发育变化的因素在很大程度上尚不清楚。由于小胶质细胞能够检测并清除凋亡细胞,因此小胶质细胞的发育变化可能受神经元凋亡的控制。在此,我们评估了发育性凋亡对小胶质细胞密度、形态、运动性和迁移的调节程度,重点关注小鼠海马体出生后的第一周,此时凋亡小体的密度在出生后第4天达到峰值,此后急剧下降。对出生后第一周原位小胶质细胞形态和分布的分析表明,虽然初级小胶质细胞分支数量变化不大,但小胶质细胞密度显著增加,并且经常可以看到小胶质细胞靠近或吞噬凋亡小体。对出生后第一周不同时间采集的海马切片进行延时成像,结果显示小胶质细胞的运动性和迁移存在差异,且这些差异与凋亡小体的密度相关。我们在缺乏凋亡的BAX基因敲除小鼠的组织中评估了这些小胶质细胞变化在多大程度上是由发育性神经元凋亡驱动的。我们发现凋亡可导致锥体细胞体层中凋亡神经元附近局部小胶质细胞聚集,但出乎意料的是,凋亡缺失并未改变体内小胶质细胞的总体密度,也未改变离体组织切片中小胶质细胞的运动性和迁移。这些结果表明,在没有发育性凋亡的情况下,小胶质细胞的形态、分布、运动性和迁移的发育变化基本正常发生,这表明除神经元凋亡外的其他因素调节了小胶质细胞发育的这些特征。