Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal.
Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
Sci Signal. 2020 Sep 22;13(650):eaba5754. doi: 10.1126/scisignal.aba5754.
Alcohol abuse adversely affects the lives of millions of people worldwide. Deficits in synaptic transmission and in microglial function are commonly found in human alcohol abusers and in animal models of alcohol intoxication. Here, we found that a protocol simulating chronic binge drinking in male mice resulted in aberrant synaptic pruning and substantial loss of excitatory synapses in the prefrontal cortex, which resulted in increased anxiety-like behavior. Mechanistically, alcohol intake increased the engulfment capacity of microglia in a manner dependent on the kinase Src, the subsequent activation of the transcription factor NF-κB, and the consequent production of the proinflammatory cytokine TNF. Pharmacological blockade of Src activation or of TNF production in microglia, genetic ablation of , or conditional ablation of microglia attenuated aberrant synaptic pruning, thereby preventing the neuronal and behavioral effects of the alcohol. Our data suggest that aberrant pruning of excitatory synapses by microglia may disrupt synaptic transmission in response to alcohol abuse.
酗酒会对全球数百万人的生活造成不良影响。在人类酗酒者和酒精中毒的动物模型中，普遍存在突触传递和小胶质细胞功能的缺陷。在这里，我们发现，模拟雄性小鼠慢性 binge drinking 的方案导致前额叶皮层的异常突触修剪和大量兴奋性突触丢失，从而导致焦虑样行为增加。从机制上讲，酒精摄入以一种依赖于激酶 Src 的方式增加了小胶质细胞的吞噬能力，随后转录因子 NF-κB 的激活和随后促炎细胞因子 TNF 的产生。Src 激活或 TNF 在小胶质细胞中的产生的药理学阻断，或小胶质细胞的基因消融或条件性消融，减弱了异常的突触修剪，从而防止了酒精对神经元和行为的影响。我们的数据表明，小胶质细胞异常修剪兴奋性突触可能会破坏对酒精滥用的突触传递。
