Cholesterol-Promoted Synaptogenesis Requires the Conversion of Cholesterol to Estradiol in the Hippocampus
Cholesterol-Promoted Synaptogenesis Requires the Conversion of Cholesterol to Estradiol in the Hippocampus
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DOI：
10.1002/hipo.20548
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发表时间：
2009-01-01
期刊：
影响因子：
3.5
通讯作者：
Rune, Gabriele M.
中科院分区：
文献类型：
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作者：
Fester, Lars;Zhou, Lepu;Rune, Gabriele M.
神经胶质来源的胆固醇促进突触发生（Mauch等人，（2001）Science 294：1354-1357）。因为在海马体中，局部雌二醇合成对于突触形成是必不可少的，我们解决了胆固醇促进突触形成是否是由于胆固醇作为雌二醇合成的前体在该脑区的功能的问题。为此，我们用胆固醇、雌二醇或来曲唑（一种有效的芳香酶抑制剂）处理海马培养物。胆固醇增加神经元雌二醇释放到介质中，在海马切片文化的棘突触的数量，和突触蛋白的免疫反应性分散的文化。同时应用胆固醇和来曲唑或阻断雌激素受体的ICI 182 780废除胆固醇诱导的突触形成。作为进一步的方法，我们通过敲低类固醇生成急性调节蛋白（类固醇生成中的限速步骤）来抑制胆固醇进入类固醇生成的第一种酶。通过雌二醇而不是胆固醇来拯救转染细胞中突触蛋白表达减少。我们的数据表明，在海马胆固醇促进突触的形成需要胆固醇转化为雌二醇。(C)2009威利-利斯公司
Cholesterol of glial origin promotes synaptogenesis (Mauch et al., (2001) Science 294:1354-1357). Because in the hippocampus local estradiol synthesis is essential for synaptogenesis, we addressed the question of whether cholesterol-promoted synapse formation results from the function of cholesterol as a precursor of estradiol synthesis in this brain area. To this end, we treated hippocampal cultures with cholesterol, estradiol, or with letrozole, a potent aromatase inhibitor. Cholesterol increased neuronal estradiol release into the medium, the number of spine synapses in hippocampal slice cultures, and immunoreactivity of synaptic proteins in dispersed cultures. Simultaneous application of cholesterol and letrozole or blockade of estrogen receptors by ICI 182 780 abolished cholesterol-induced synapse formation. As a further approach, we inhibited the access of cholesterol to the first enzyme of steroidogenesis by knock-down of steroidogenic acute regulatory protein, the rate-limiting step in steroidogenesis. A rescue of reduced synaptic protein expression in transfected cells was achieved by estradiol but not by cholesterol. Our data indicate that in the hippocampus cholesterol-promoted synapse formation requires the conversion of cholesterol to estradiol. (C) 2009 Wiley-Liss, Inc.