Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211.
J Neurosci. 2013 Sep 18;33(38):15184-94. doi: 10.1523/JNEUROSCI.1716-13.2013.
Our laboratory has demonstrated that 17β-estradiol (E2) enhances hippocampal memory consolidation via rapid activation of multiple intracellular signaling cascades, including the ERK/MAPK cascade (Fernandez et al., 2008; Fan et al., 2010). However, the receptor mechanisms responsible for these effects of E2 remain unclear. In vitro, estrogen receptor α (ERα) signaling through metabotropic glutamate receptor 1a (mGluR1a) leads to ERK-dependent CREB phosphorylation (Boulware et al., 2005), suggesting that interactions between ERs and mGluR1a may be vital to the memory-enhancing effects of E2. As such, the present study tested the roles of classical estrogen receptors (ERα and ERβ) and mGluR1a in mediating the effects of E2 on hippocampal memory consolidation. Dorsal hippocampal (DH) infusion of ERα (PPT) or ERβ (DPN) agonists enhanced novel object recognition and object placement memory in ovariectomized female mice in an ERK-dependent manner, suggesting that these receptors influence memory by rapidly activating hippocampal cell signaling. Next, DH infusion of the mGluR1a antagonist LY367385 blocked the object and spatial memory facilitation induced by E2, PPT, and DPN, demonstrating that ER/mGluR1a signaling is critical for the memory-enhancing effects of E2. Finally, we show that ERα, ERβ, mGluR1, and ERK all reside within specialized membrane microdomains of the DH, and that ERα and ERβ physically interact with mGluR1, providing a means through which ERs may activate mGluRs and downstream signaling. Together, these findings provide the first in vivo evidence demonstrating that ER/mGluR signaling can mediate the beneficial effects of E2 on hippocampal memory consolidation.
我们的实验室已经证明，17β-雌二醇（E2）通过快速激活多种细胞内信号级联反应，包括 ERK/MAPK 级联反应（Fernandez 等人，2008 年；Fan 等人，2010 年），增强海马体记忆巩固。然而，负责这些 E2 作用的受体机制尚不清楚。在体外，雌激素受体α（ERα）通过代谢型谷氨酸受体 1a（mGluR1a）信号导致 ERK 依赖性 CREB 磷酸化（Boulware 等人，2005 年），表明 ER 和 mGluR1a 之间的相互作用对于 E2 的增强记忆作用可能至关重要。因此，本研究测试了经典雌激素受体（ERα和 ERβ）和 mGluR1a 在介导 E2 对海马体记忆巩固的作用。背海马体（DH）中 ERα（PPT）或 ERβ（DPN）激动剂的输注以 ERK 依赖性方式增强了去卵巢雌性小鼠的新物体识别和物体放置记忆，表明这些受体通过快速激活海马体细胞信号来影响记忆。接下来，DH 中 mGluR1a 拮抗剂 LY367385 的输注阻断了 E2、PPT 和 DPN 诱导的物体和空间记忆改善，表明 ER/mGluR1a 信号对于 E2 的增强记忆作用至关重要。最后，我们表明 ERα、ERβ、mGluR1 和 ERK 都存在于 DH 的专门膜微域中，并且 ERα 和 ERβ 与 mGluR1 物理相互作用，为 ER 可能激活 mGluRs 和下游信号提供了一种手段。总之，这些发现提供了体内证据，证明 ER/mGluR 信号可以介导 E2 对海马体记忆巩固的有益作用。
