Ahlers Katelin E, Karaçay Bahri, Fuller Leah, Bonthius Daniel J, Dailey Michael E
Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, Iowa.
Division of Child Neurology, Department of Pediatrics, University of Iowa, Iowa City, Iowa.
Glia. 2015 Oct;63(10):1694-713. doi: 10.1002/glia.22835. Epub 2015 Apr 9.
Fetal alcohol exposure is the most common known cause of preventable mental retardation, yet we know little about how microglia respond to, or are affected by, alcohol in the developing brain in vivo. Using an acute (single day) model of moderate (3 g/kg) to severe (5 g/kg) alcohol exposure in postnatal day (P) 7 or P8 mice, we found that alcohol-induced neuroapoptosis in the neocortex is closely correlated in space and time with the appearance of activated microglia near dead cells. The timing and molecular pattern of microglial activation varied with the level of cell death. Although microglia rapidly mobilized to contact and engulf late-stage apoptotic neurons, apoptotic bodies temporarily accumulated in neocortex, suggesting that in severe cases of alcohol toxicity the neurodegeneration rate exceeds the clearance capacity of endogenous microglia. Nevertheless, most dead cells were cleared and microglia began to deactivate within 1-2 days of the initial insult. Coincident with microglial activation and deactivation, there was a transient increase in expression of pro-inflammatory factors, TNFα and IL-1β, after severe (5 g/kg) but not moderate (3 g/kg) EtOH levels. Alcohol-induced microglial activation and pro-inflammatory factor expression were largely abolished in BAX null mice lacking neuroapoptosis, indicating that microglial activation is primarily triggered by apoptosis rather than the alcohol. Therefore, acute alcohol exposure in the developing neocortex causes transient microglial activation and mobilization, promoting clearance of dead cells and tissue recovery. Moreover, cortical microglia show a remarkable capacity to rapidly deactivate following even severe neurodegenerative insults in the developing brain.
胎儿酒精暴露是已知可预防的智力迟钝的最常见原因，但我们对小胶质细胞在发育中的大脑中如何响应酒精或受其影响知之甚少。利用出生后第7天或第8天的小鼠进行中度（3 g/kg）至重度（5 g/kg）酒精暴露的急性（单日）模型，我们发现酒精诱导的新皮质神经细胞凋亡在空间和时间上与死亡细胞附近活化小胶质细胞的出现密切相关。小胶质细胞活化的时间和分子模式随细胞死亡水平而变化。尽管小胶质细胞迅速移动以接触并吞噬晚期凋亡神经元，但凋亡小体暂时积聚在新皮质中，这表明在酒精毒性严重的情况下，神经退行性变的速度超过了内源性小胶质细胞的清除能力。然而，大多数死亡细胞在最初损伤后的1 - 2天内被清除，小胶质细胞开始失活。与小胶质细胞的活化和失活同时发生的是，在重度（5 g/kg）而非中度（3 g/kg）乙醇水平后，促炎因子TNFα和IL - 1β的表达出现短暂增加。在缺乏神经细胞凋亡的BAX基因敲除小鼠中，酒精诱导的小胶质细胞活化和促炎因子表达在很大程度上被消除，这表明小胶质细胞的活化主要是由细胞凋亡而非酒精触发的。因此，发育中的新皮质急性酒精暴露会导致小胶质细胞短暂活化和移动，促进死亡细胞的清除和组织恢复。此外，皮质小胶质细胞显示出在发育中的大脑中即使受到严重神经退行性损伤后也能迅速失活的显著能力。
