Sugiyama N, Andersson S, Lathe R, Fan X, Alonso-Magdalena P, Schwend T, Nalvarte I, Warner M, Gustafsson J-A
Department of Biosciences and Nutrition, Karolinska Institute, Novum, Huddinge, Sweden.
Mol Psychiatry. 2009 Feb;14(2):223-32, 117. doi: 10.1038/mp.2008.118. Epub 2008 Nov 4.
This study reports on the spatiotemporal dynamics of the expression of estrogen receptors (ERs) in the mouse central nervous system (CNS) during the early postnatal and the peripubertal period. At postnatal day 7 (P7), neurons with strong nuclear immunostaining for both ERalpha and ERbeta1 were widely distributed throughout the brain. Sucrose density gradient sedimentation followed by western blotting supported the histochemical evidence for high levels of both ERs at P7. Over the following 2 days, there was a rapid downregulation of ERs. At P9, ERalpha expression was visible only in the hypothalamic area. Decline in ERbeta1 expression was slower than that of ERalpha, and ERalpha-negative, ERbeta1-positive cells were observed in the dentate gyrus and walls of third ventricle. Between P14 and P35, ERs were undetectable except for the hypothalamic area. As before P7, the ovary does not produce estrogen but does produce 5alpha-androstane-3beta, 17beta-diol (3betaAdiol), an estrogenic metabolite of dihydrotestosterone, we examined the effects of high levels of 3betaAdiol in the postnatal period. We used CYP7B1 knockout mice which cannot hydroxylate and inactivate 3betaAdiol. The brains of these mice are abnormally large with reduced apoptosis. In the early postnatal period, there was 1-week delay in the timing of the reduction in ER expression in the brain. These data reveal that the time when ERs might be activated in the brain is limited to the first 8 postnatal days. In addition, the importance of aromatase has to be reconsidered as the alternative estrogen, 3betaAdiol, is important in neuronal function in the postnatal brain.
本研究报告了出生后早期和青春期前后小鼠中枢神经系统（CNS）中雌激素受体（ERs）表达的时空动态变化。在出生后第7天（P7），对ERα和ERβ1均有强核免疫染色的神经元广泛分布于整个大脑。蔗糖密度梯度沉降后进行蛋白质印迹分析，支持了P7时两种ERs水平均高的组织化学证据。在接下来的2天里，ERs迅速下调。在P9时，ERα表达仅在下丘脑区域可见。ERβ1表达的下降比ERα慢，在齿状回和第三脑室壁观察到ERα阴性、ERβ1阳性细胞。在P14至P35之间，除下丘脑区域外，未检测到ERs。如在P7之前一样，卵巢不产生雌激素，但会产生5α-雄甾烷-3β,17β-二醇（3βAdiol），这是二氢睾酮的一种雌激素代谢物，我们研究了出生后时期高水平3βAdiol的影响。我们使用了不能使3βAdiol羟基化并使其失活的CYP7B1基因敲除小鼠。这些小鼠的大脑异常大，细胞凋亡减少。在出生后早期，大脑中ER表达减少的时间延迟了1周。这些数据表明，大脑中ERs可能被激活的时间仅限于出生后的前8天。此外，由于替代雌激素3βAdiol在出生后大脑的神经元功能中很重要，芳香化酶的重要性必须重新考虑。
