TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment
TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment
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DOI：
10.1016/j.bbi.2014.11.015
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发表时间：
2015-03-01
影响因子：
15.1
通讯作者：
Guerri, Consuelo
中科院分区：
文献类型：
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作者：
Montesinos, Jorge;Pascual, Maria;Guerri, Consuelo
青春期的大脑经历了重要的动态和可塑性细胞变化，包括轴突和突触的过度产生，然后随着轴突髓鞘形成的进行而沿着快速修剪。这些发育变化使青少年的大脑特别容易受到酒精的神经毒性和行为影响。虽然这些作用的机制在很大程度上是未知的，我们证明，乙醇通过激活先天免疫受体toll样受体4（TLR 4），诱导成年小鼠的神经炎症和脑损伤。本研究旨在评估青春期间歇性乙醇治疗是否会促进TLR 4依赖性促炎过程，导致髓鞘和突触功能障碍以及长期认知障碍。使用野生型（WT）和TLR 4缺陷（TLR 4-KO）的青春期小鼠间歇性地用乙醇（3.0 g/kg）处理2周，我们表明，酗酒样乙醇处理激活TLR 4信号通路（MAPK，NP κ B），导致细胞因子和促炎介质（考克斯-2，iNOS，HMGB 1）的上调，损害突触和髓鞘蛋白水平，并引起超微结构改变。这些变化与年轻成年小鼠的长期认知功能障碍有关，如物体识别，被动回避和嗅觉行为测试所示。值得注意的是，TLR 4受体的消除阻止了神经炎症沿着突触和髓鞘紊乱，以及长期认知改变。这些结果支持神经免疫反应和TLR 4信号在青春期乙醇的神经毒性和行为影响中的作用。(C)2014爱思唯尔公司All rights reserved.
The adolescent brain undergoes important dynamic and plastic cell changes, including overproduction of axons and synapses, followed by rapid pruning along with ongoing axon myelination. These developmental changes make the adolescent brain particularly vulnerable to neurotoxic and behavioral effects of alcohol. Although the mechanisms of these effects are largely unknown, we demonstrated that ethanol by activating innate immune receptors toll-like receptor 4 (TLR4), induces neuroinflammation and brain damage in adult mice. The present study aims to evaluate whether intermittent ethanol treatment in adolescence promotes TLR4-dependent pro-inflammatory processes, leading to myelin and synaptic dysfunctions, and long-term cognitive impairments. Using wild-type (WT) and TLR4-deficient (TLR4-KO) adolescent mice treated intermittently with ethanol (3.0 g/kg) for 2 weeks, we show that binge-like ethanol treatment activates TLR4 signaling pathways (MAPK, NP kappa B) leading to the up-regulation of cytokines and pro-inflammatory mediators (COX-2, iNOS, HMGB1), impairing synaptic and myelin protein levels and causing ultrastructural alterations. These changes were associated with long-lasting cognitive dysfunctions in young adult mice, as demonstrated with the object recognition, passive avoidance and olfactory behavior tests. Notably, elimination of TLR4 receptors prevented neuroinflammation along with synaptic and myelin derangements, as well as long-term cognitive alterations. These results support the role of the neuroimmune response and TLR4 signaling in the neurotoxic and behavioral effects of ethanol in adolescence. (C) 2014 Elsevier Inc. All rights reserved.