Early-Life Stress Perturbs Key Cellular Programs in the Developing Mouse Hippocampus.
Early-Life Stress Perturbs Key Cellular Programs in the Developing Mouse Hippocampus.
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DOI：
10.1159/000430861
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发表时间：
2015
影响因子：
2.9
通讯作者：
Kaffman A
中科院分区：
文献类型：
--
作者：
Wei L;Hao J;Lacher RK;Abbott T;Chung L;Colangelo CM;Kaffman A
关于儿童期虐待和忽视对儿童海马体功能的影响，已有相关报告。虽然早期的成像研究和一些动物研究表明，早期生活压力（ELS）的影响只表现在成年期，但最近的研究表明，虐待儿童和青少年的海马功能受损。需要使用动物模式的额外工作来阐明ELS对海马发育的影响。在这方面，基因组学，蛋白质组学和分子工具独特的小鼠使其成为一个特别有吸引力的模型系统来研究这个问题。然而，到目前为止，很少有工作已经做了表征ELS对小鼠海马发育的影响。为了解决这个问题，我们研究了短暂的每日分离（BDS），ELS的小鼠模型，损害海马依赖的记忆在成年期，海马发育在28日龄的幼年小鼠的影响。之所以选择这个年龄，是因为它对应于人类成像研究显示受虐待儿童海马发育异常的发育时期。暴露于BDS导致从28日龄雄性和雌性小鼠的海马收获的突触体的总蛋白含量显著降低，表明BDS损害幼年海马中的正常突触发育。使用一种新的液相色谱多反应监测质谱（LC-MRM）分析，我们发现许多突触蛋白的表达减少，以及参与轴突生长，髓鞘形成和线粒体活性的蛋白质。28天龄BDS小鼠的高尔基体染色显示，CA 1神经元中未成熟和形状异常的棘的数量增加，成熟棘的数量减少，这与该年龄的突触成熟和突触修剪缺陷一致。在14日龄的幼崽，BDS的表达参与轴突生长和髓鞘，但不影响总蛋白含量的突触体收获海马，或其他突触标志物的蛋白质水平。这些结果为该领域以前的工作增加了两个重要发现。首先，我们的研究结果表明，在28日龄的幼龄小鼠中，BDS损害突触成熟，并减少轴突生长，髓鞘形成和线粒体功能所必需的蛋白质的表达。第二，研究结果表明，在一个连续的模型中，BDS损害正常的轴突生长和髓鞘形成之前，它破坏了青少年海马中的突触成熟。
Conflicting reports are available with regard to the effects of childhood abuse and neglect on hippocampal function in children. While earlier imaging studies and some animal work suggested that the effects of early life stress (ELS) manifest only in adulthood, more recent studies have documented impaired hippocampal function in maltreated children and adolescents. Additional work using animal modes is needed to clarify the effects of ELS on hippocampal development. In this regard, genomic, proteomic, and molecular tools uniquely available in the mouse make it a particularly attractive model system to study this issue. However, very little work has been done so far to characterize the effects of ELS on hippocampal development in the mouse. To address this issue, we examined the effects of brief daily separation (BDS), a mouse model of ELS that impairs hippocampal-dependent memory in adulthood, on hippocampal development in 28-day old juvenile mice. This age was chosen because it corresponds to the developmental period in which human imaging studies have revealed abnormal hippocampal development in maltreated children. Exposure to BDS caused a significant decrease in the total protein content of synaptosomes harvested from the hippocampus of 28-day old male and female mice suggesting that BDS impairs normal synaptic development in the juvenile hippocampus. Using a novel liquid chromatography multiple reactions monitoring mass spectrometry (LC-MRM) assay, we found decreased expression of many synaptic proteins, as well as proteins involved in axonal growth, myelination, and mitochondrial activity. Golgi staining in 28-day old BDS mice showed an increase in the number of immature and abnormally shaped spines and a decrease in the number of mature spines in CA1 neurons, consistent with defects in synaptic maturation and synaptic pruning at this age. In 14-day old pups, BDS deceased the expression of proteins involved in axonal growth and myelination, but did not affect the total protein content of synaptosomes harvested from the hippocampus, or protein levels of other synaptic markers. These results add two important findings to previous work in the field. First, our findings demonstrate that in 28-day old juvenile mice, BDS impairs synaptic maturation and reduces the expression of proteins that are necessary for axonal growth, myelination, and mitochondrial function. Second, the results suggest a sequential model in which BDS impairs normal axonal growth and myelination before it disrupts synaptic maturation in the juvenile hippocampus.