Prenatal Alcohol Exposure Modifies Glucocorticoid Receptor Subcellular Distribution in the Medial Prefrontal Cortex and Impairs Frontal Cortex-Dependent Learning
Prenatal Alcohol Exposure Modifies Glucocorticoid Receptor Subcellular Distribution in the Medial Prefrontal Cortex and Impairs Frontal Cortex-Dependent Learning
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DOI：
10.1371/journal.pone.0096200
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发表时间：
2014-04-22
期刊：
影响因子：
3.7
通讯作者：
Caldwell, Kevin K.
中科院分区：
文献类型：
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作者：
Allan, Andrea M.;Goggin, Samantha L.;Caldwell, Kevin K.
产前酒精暴露(PAE)已被证明会损害儿童的学习、记忆和执行功能。坚持不懈，或未能对不断变化的意外情况做出适应性反应，是人类胎儿酒精谱系障碍(FASD)神经行为评估任务的标志。适应性反应主要是内侧前额叶皮质(MPFC)的产物，受皮质类固醇的调节。在我们的PAE小鼠模型中，我们最近报道了海马区依赖学习和记忆的缺陷，以及海马区糖皮质激素受体(GR)亚细胞分布的失调。在这里，我们研究了PAE对额叶皮质依赖行为的影响，以及mPFC GR亚细胞分布和细胞内GR运输调节因子的水平。在Y迷宫反转学习任务中，PAE小鼠的反应灵活性显著降低。PAE mPFC核内总糖皮质激素受体水平降低，丝氨酸203、211和226位磷酸化的糖皮质激素受体水平无明显变化。在PAE mPFC中，胞浆MR水平升高，但不是细胞核MR水平升高。PAE小鼠体内关键的GR转运蛋白FKBP51、Hsp90、亲环素40、动力蛋白和动力蛋白中间链的水平发生改变，有利于GR被排除在细胞核外，提示GR转运功能失调。我们的发现表明，在出生前酒精暴露的小鼠中，GR核定位缺陷与额叶皮质学习障碍之间可能存在联系。
Prenatal alcohol exposure (PAE) has been shown to impair learning, memory and executive functioning in children. Perseveration, or the failure to respond adaptively to changing contingencies, is a hallmark on neurobehavioral assessment tasks for human fetal alcohol spectrum disorder (FASD). Adaptive responding is predominantly a product of the medial prefrontal cortex (mPFC) and is regulated by corticosteroids. In our mouse model of PAE we recently reported deficits in hippocampal formation-dependent learning and memory and a dysregulation of hippocampal formation glucocorticoid receptor (GR) subcellular distribution. Here, we examined the effect of PAE on frontal cortical-dependent behavior, as well as mPFC GR subcellular distribution and the levels of regulators of intracellular GR transport. PAE mice displayed significantly reduced response flexibility in a Y-maze reversal learning task. While the levels of total nuclear GR were reduced in PAE mPFC, levels of GR phosphorylated at serines 203, 211 and 226 were not significantly changed. Cytosolic, but not nuclear, MR levels were elevated in the PAE mPFC. The levels of critical GR trafficking proteins, FKBP51, Hsp90, cyclophilin 40, dynamitin and dynein intermediate chain, were altered in PAE mice, in favor of the exclusion of GR from the nucleus, indicating dysregulation of GR trafficking. Our findings suggest that there may be a link between a deficit in GR nuclear localization and frontal cortical learning deficits in prenatal alcohol-exposed mice.