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Daily alcohol intake triggers aberrant synaptic pruning leading to synapse loss and anxiety-like behavior.
Science Signaling ( IF 6.7 ) Pub Date : 2020-09-22 , DOI: 10.1126/scisignal.aba5754
Renato Socodato 1 , Joana F Henriques 1 , Camila C Portugal 1 , Tiago O Almeida 1 , Joana Tedim-Moreira 1 , Renata L Alves 1 , Teresa Canedo 1, 2 , Cátia Silva 1 , Ana Magalhães 1 , Teresa Summavielle 1 , João B Relvas 1, 2
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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 Tnf, 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.



中文翻译:

每日饮酒会触发异常的突触修剪,导致突触丢失和焦虑样行为。

酗酒对全世界数百万人的生活产生不利影响。突触传递和小胶质细胞功能缺陷常见于人类酗酒者和酒精中毒动物模型。在这里,我们发现模拟雄性小鼠慢性酗酒的方案导致异常突触修剪和前额叶皮层兴奋性突触的大量丧失,从而导致焦虑样行为增加。从机制上讲,酒精摄入以依赖激酶 Src、转录因子 NF-κB 的随后激活以及随后促炎细胞因子 TNF 的产生的方式增加了小胶质细胞的吞噬能力。小胶质细胞中 Src 激活或 TNF 产生的药理学阻断,Tnf 的遗传消融,或小胶质细胞的有条件消融减弱了异常突触修剪,从而防止了酒精对神经元和行为的影响。我们的数据表明,小胶质细胞对兴奋性突触的异常修剪可能会破坏对酒精滥用的突触传递。

更新日期:2020-09-23
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