Local neurosteroid production in the hippocampus: Influence on synaptic plasticity of memory
Local neurosteroid production in the hippocampus: Influence on synaptic plasticity of memory
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DOI：
10.1159/000097747
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发表时间：
2006-01-01
影响因子：
4.1
通讯作者：
Kawato, Suguru
中科院分区：
文献类型：
--
作者：
Mukai, Hideo;Tsurugizawa, Tomokazu;Kawato, Suguru
在神经内分泌学中，人们认为类固醇激素在性腺和/或肾上腺中合成，并通过血液循环到达大脑。与这一观点相反，我们正在证明雌激素和雄激素也是由海马中的细胞色素 P450 局部合成的，并且这些类固醇可以快速调节神经元突触可塑性。我们证明雌激素是在成年海马神经元中局部合成的。在类固醇生成途径中，胆固醇转化为孕烯醇酮（通过 P450scc）、脱氢表雄酮 [通过 P450(17 α)]、雄烯二醇（通过 17 β-羟基类固醇脱氢酶、17 β-HSD）、睾酮（通过 3 β-HSD），最后转化为雌二醇（通过 P450arom）和二氢睾酮（通过 5）。 α-还原酶）。海马中雌二醇的基础浓度约为1 nM，高于血浆中的浓度。 RT-PCR证明了P450scc、P450(17α)、P450arom、17β-HSD、3β-HSD和5α-还原酶的mRNA的显着表达。它们在海马体中的mRNA水平是内分泌器官中的1/200-1/5,000。使用免疫电子显微镜，除了主要神经元的内质网外，还观察到 P450(17α) 和 P450arom 的定位在突触中。与性腺雌二醇通过血液循环到达大脑的缓慢作用不同，海马神经元源性雌二醇可以在神经元内局部快速作用。例如，1 nM 17 β-雌二醇不仅迅速增强 CA1 的长期抑制 (LTD)，而且还迅速增强 CA3 和齿状回的长期抑制 (LTD)。在 CA1 锥体神经元中应用 1 nM 雌二醇后，细棘的密度在 2 小时内选择性增加。只有 ER α 激动剂丙基吡唑三基苯酚对 CA1 中的 LTD 和棘生成具有与雌二醇相同的增强作用。 ER β 激动剂羟苯基丙腈抑制 LTD，但不影响脊柱生成。除了主要神经元的细胞核外，雌激素受体 ER α 还定位在脊柱中，这意味着突触 ER α 可以通过内源性雌二醇驱动突触可塑性的快速调节。版权所有 (c) 2006 S. Karger AG，巴塞尔。
In neuroendocrinology, it is believed that steroid hormones are synthesized in the gonads and/or adrenal glands, and reach the brain via the blood circulation. In contrast to this view, we are in progress of demonstrating that estrogens and androgens are also synthesized locally by cytochrome P450s in the hippocampus, and that these steroids act rapidly to modulate neuronal synaptic plasticity. We demonstrated that estrogens were locally synthesized in the adult hippocampal neurons. In the pathway of steroidogenesis, cholesterol is converted to pregnenolone (by P450scc), dehydroepiandrosterone [by P450(17 alpha)], androstenediol (by 17 beta-hydroxysteroid dehydrogenase, 17 beta-HSD), testosterone (by 3 beta-HSD) and finally to estradiol (by P450arom) and dihydrotestosterone (by 5 alpha-reductase). The basal concentration of estradiol in the hippocampus was approximately 1 nM, which was greater than that in blood plasma. Significant expression of mRNA for P450scc, P450(17 alpha), P450arom, 17 beta-HSD, 3 beta-HSD and 5 alpha-reductase was demonstrated by RT-PCR. Their mRNA levels in the hippocampus were 1/200-1/5,000 of those in the endocrine organs. Localization of P450(17 alpha) and P450arom was observed in synapses in addition to endoplasmic reticulum of principal neurons using immunoelectron microscopy. Different from slow action of gonadal estradiol which reaches the brain via the blood circulation, hippocampal neuron-derived estradiol may act locally and rapidly within the neurons. For example, 1 nM 17 beta-estradiol rapidly enhanced the long-term depression (LTD) not only in CA1 but also in CA3 and dentate gyrus. The density of thin spines was selectively increased within 2 h upon application of 1 nM estradiol in CA1 pyramidal neurons. Only ER alpha agonist propyl-pyrazole-trinyl-phenol induced the same enhancing effect as estradiol on both LTD and spinogenesis in the CA1. ER beta agonist hydroxyphenyl-propionitrile suppressed LTD and did not affect spinogenesis. Localization of estrogen receptor ER alpha in spines in addition to nuclei of principal neurons implies that synaptic ER alpha can drive rapid modulation of synaptic plasticity by endogenous estradiol. Copyright (c) 2006 S. Karger AG, Basel.