Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation.
Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation.
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DOI：
10.1523/jneurosci.4333-09.2010
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发表时间：
2010-03-24
期刊：
影响因子：
--
通讯作者：
Frick KM
中科院分区：
文献类型：
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作者：
Fan L;Zhao Z;Orr PT;Chambers CH;Lewis MC;Frick KM
我们先前的研究表明，17-雌二醇(17β-estadiol，E_2)是增强去卵巢小鼠新物体识别所必需的信号调节蛋白激酶。在这里，我们询问E2在中年和老年去卵巢小鼠中是否具有类似的记忆增强作用，以及这些作用是否依赖于ERK和磷脂酰肌醇3-激酶(PI3K)/Akt的激活。我们首次证明了在物体识别训练后立即注入脑室(ICV)或海马区(IH)E2增强了中年女性的记忆巩固，而不是老年女性。IH抑制ERK或PI3K的激活可阻断雌激素E_2对中年女性的增强作用。中年女性接受iH或icv E2注射后5分钟，背侧海马区p42 ERK的磷酸化水平增加，但不增加5分钟，这种作用可被IH抑制ERK或PI3K的激活所阻断。中年女性注射IH或icv E_2 5min后，背侧海马PI3K和Akt的磷酸化水平升高，而老年女性则未见明显变化。脑室注射E_2后15min，PI3K的磷酸化也增加，这种作用可被IH的PI3K抑制所阻断，但不能阻断ERK。这些数据首次表明，激活背侧海马PI3K/Akt和ERK信号通路是E2增强中年女性物体识别记忆所必需的。他们还揭示了类似的背侧海马区信号通路介导了E2诱导的中青年女性物体识别记忆的增强，而E2无法激活这些通路可能是其未能增强老年女性物体识别的原因。
We previously demonstrated that dorsal hippocampal extracellular signal-regulated kinase (ERK) activation is necessary for 17β-estradiol (E2) to enhance novel object recognition in young ovariectomized mice. Here, we asked whether E2 has similar memory-enhancing effects in middle-aged and aged ovariectomized mice, and whether these effects depend on ERK and phosphatidylinositol 3-kinase (PI3K)/Akt activation. We first demonstrated that intracerebroventricular (ICV) E2 or intrahippocampal (IH) E2 infusion immediately after object recognition training enhanced memory consolidation in middle-aged, but not aged, females. The E2-induced enhancement in middle-aged females was blocked by IH inhibition of ERK or PI3K activation. IH or ICV E2 infusion in middle-aged females increased phosphorylation of p42 ERK in the dorsal hippocampus 15, but not 5, min after infusion, an effect that was blocked by IH inhibition of ERK or PI3K activation. Dorsal hippocampal PI3K and Akt phosphorylation was increased 5 min after IH or ICV E2 infusion in middle-aged, but not aged, females. ICV E2 infusion also increased PI3K phosphorylation after 15 min, and this effect was blocked by IH PI3K, but not ERK, inhibition. These data demonstrate for the first time that activation of dorsal hippocampal PI3K/Akt and ERK signaling pathways is necessary for E2 to enhance object recognition memory in middle-aged females. They also reveal that similar dorsal hippocampal signaling pathways mediate E2-induced object recognition memory enhancement in young and middle-aged females, and that the inability of E2 to activate these pathways may underlie its failure to enhance object recognition in aged females.