Prenatal alcohol exposure is associated with altered subcellular distribution of glucocorticoid and mineralocorticoid receptors in the adolescent mouse hippocampal formation.
Prenatal alcohol exposure is associated with altered subcellular distribution of glucocorticoid and mineralocorticoid receptors in the adolescent mouse hippocampal formation.
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DOI：
10.1111/acer.12236
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发表时间：
2014-02
期刊：
影响因子：
--
通讯作者：
Allan AM
中科院分区：
文献类型：
--
作者：
Caldwell KK;Goggin SL;Tyler CR;Allan AM
越来越多的证据表明，产前酒精暴露（PAE）的一些长期后果是皮质边缘结构（包括海马形成）发育和功能变化的结果。糖皮质激素受体（GR）和矿皮质激素受体（MR）是海马形成发育、结构和功能的关键调节因子，因此是PAE对该脑区影响的潜在介质。在本研究中，我们评估了PAE对小鼠海马形成中皮质类固醇信号通路成分的影响。在整个怀孕期间，给小鼠提供10% （w/v）含0.066% （w/v）糖精（SAC）或0.066% （w/v）糖精的乙醇，使用有限的（4小时）通道，在黑暗中饮用。从naïve出生后40至50天的后代中分离海马结构，并制备亚细胞组分。利用免疫印迹技术，我们检测了GR、MR、11-β-羟基类固醇脱氢酶1 （11β- hsd1）和fk506结合蛋白51 （FKBP51、FKBP5）和52 （FKBP52、FKBP4）的水平。最后，我们确定了PAE对情境辨别的影响，情境辨别是海马依赖的学习/记忆任务。PAE与海马结构中MR降低和GR核定位升高相关，而这两种受体的细胞质水平没有显著改变。FKBP51水平降低，而FKBP52水平不变，而11β-HSD1水平在PAE小鼠海马形成中分离的核后组分中升高。这些神经化学变化与环境歧视的减少有关。这些数据支持一个模型，在该模型中，PAE导致青春期小鼠海马形成中FKBP51减少和11β-HSD1水平增加的继发GRs核定位增加。预计GR亚细胞分布的持续失调会损害海马的形成，并可能是PAE对海马依赖功能的许多影响的基础。
Accumulating evidence indicates that several of the long-term consequences of prenatal alcohol exposure (PAE) are the result of changes in the development and function of cortico-limbic structures, including the hippocampal formation. The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are key regulators of hippocampal formation development, structure, and functioning and, thus, are potential mediators of PAE’s effects on this brain region. In the present studies, we assessed the impact of PAE on components of corticosteroid signaling pathways in the mouse hippocampal formation. Throughout pregnancy, mouse dams were offered either 10% (w/v) ethanol sweetened with 0.066% (w/v) saccharin (SAC) or 0.066% (w/v) SAC alone using a limited (4-hour) access, drinking-in-the-dark paradigm. The hippocampal formation was isolated from naïve postnatal day 40 to 50 offspring, and subcellular fractions were prepared. Using immunoblotting techniques, we measured the levels of GR, MR, 11-β-hydroxysteroid dehydrogenase 1 (11β-HSD1), and the FK506-binding proteins 51 (FKBP51, FKBP5) and 52 (FKBP52, FKBP4). Finally, we determined the effect of PAE on context discrimination, a hippocampal-dependent learning/memory task. PAE was associated with reduced MR and elevated GR nuclear localization in the hippocampal formation, whereas cytosolic levels of both receptors were not significantly altered. FKBP51 levels were reduced, while FKBP52 levels were unaltered, and 11β-HSD1 levels were increased in postnuclear fractions isolated from PAE mouse hippocampal formation. These neurochemical alterations were associated with reduced context discrimination. The data support a model in which PAE leads to increased nuclear localization of GRs secondary to reductions in FKBP51 and increases in 11β-HSD1 levels in the adolescent mouse hippocampal formation. Persistent dysregulation of GR subcellular distribution is predicted to damage the hippocampal formation and may underlie many of the effects of PAE on hippocampal-dependent functioning.
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影响因子：
5.3
作者：
Galigniana, Mario D.;Erlejman, Alejandra G.;Piwien-Pilipuk, Graciela
通讯作者：
Piwien-Pilipuk, Graciela
影响因子：
3.3
作者：
Hodes, G. E.;Brookshire, B. R.;Hill-Smith, T. E.;Teegarden, S. L.;Berton, O.;Lucki, I.
通讯作者：
Lucki, I.
影响因子：
5.2
作者：
Jankord R;Herman JP
通讯作者：
Herman JP
DOI：
10.1523/jneurosci.1692-12.2012
发表时间：
2012-06-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kheirbek MA;Tannenholz L;Hen R
通讯作者：
Hen R
影响因子：
8.2
作者：
Andersen, SL
通讯作者：
Andersen, SL