Nuñez Joseph L, Aberdeen Graham W, Albrecht Eugene D, McCarthy Margaret M
Department of Physiology, University of Maryland, Baltimore, Baltimore, Maryland 21201, USA.
Endocrinology. 2008 Dec;149(12):6433-43. doi: 10.1210/en.2007-1720. Epub 2008 Aug 14.
High levels of maternal estrogens are likely to gain access to the fetal brain, yet little is known regarding the role of the steroid hormone 17beta-estradiol in neuronal differentiation and maturation of primate neurons. Previous research documented the presence of estrogen receptors during development in the hippocampus and cortex of the primate brain, but the functional significance of steroid exposure has not been widely investigated. Using both an in vitro preparation of primary hippocampal and frontal cortex neurons and Western blot analysis of fetal hippocampal and frontal cortex tissue, we documented the effects of in utero and acute in vitro exposure to 17beta-estradiol on the development of neuronal responsiveness to the amino acid transmitters gamma-aminobutyric acid (GABA) and glutamate in fetal baboon, Papio anubis, hippocampal, and cortical neurons. We found that in utero 17beta-estradiol exposure enhanced the excitatory action of the GABAergic system on immature cortical and hippocampal neurons, as manifest by increases in intracellular calcium after transient muscimol application and changes in the relevant ion cotransporters. Acute exposure to 17beta-estradiol in vitro had limited effect on GABAergic responses in cultured hippocampal and frontal cortex neurons. Moreover, there was limited effect of both prolonged in utero and acute estradiol on the response to glutamatergic system activation, consistent with previous findings in the rat. Along with documenting a prominent role for 17beta-estradiol in maturation of the GABAergic system, these findings increase our understanding of neuronal differentiation and maturation in the fetal primate brain.
高水平的母体雌激素很可能进入胎儿大脑,但关于类固醇激素17β-雌二醇在灵长类神经元的神经分化和成熟过程中的作用,人们知之甚少。先前的研究记录了灵长类动物大脑海马体和皮质发育过程中雌激素受体的存在,但类固醇暴露的功能意义尚未得到广泛研究。我们使用原代海马体和额叶皮质神经元的体外制备方法以及对胎儿海马体和额叶皮质组织的蛋白质免疫印迹分析,记录了子宫内和体外急性暴露于17β-雌二醇对胎儿东非狒狒(Papio anubis)海马体和皮质神经元对氨基酸递质γ-氨基丁酸(GABA)和谷氨酸的神经元反应性发育的影响。我们发现,子宫内暴露于17β-雌二醇增强了GABA能系统对未成熟皮质和海马体神经元的兴奋作用,短暂应用蝇蕈醇后细胞内钙增加以及相关离子共转运体的变化就表明了这一点。体外急性暴露于17β-雌二醇对培养的海马体和额叶皮质神经元的GABA能反应影响有限。此外,子宫内长期暴露和急性暴露于雌二醇对谷氨酸能系统激活反应的影响都有限,这与先前在大鼠中的研究结果一致。这些发现不仅证明了17β-雌二醇在GABA能系统成熟中起重要作用,还增进了我们对胎儿灵长类动物大脑中神经元分化和成熟的理解。