Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
Brain Res. 2011 Mar 16;1379:53-60. doi: 10.1016/j.brainres.2010.11.098. Epub 2010 Dec 5.
Beneficial effects of estrogen therapy on cognitive performance diminish with age and time following the loss of ovarian function. This has led to the 'Window of Opportunity' hypothesis, which states that estrogen therapy must be administered within a limited period of time following menopause in order to be effective. Effects of estrogen therapy on cognitive performance are due, at least in part, to the effects on cholinergic afferents innervating the hippocampus and cortex, and it has been suggested that the loss of estrogen effect with age and time following menopause is due to a substantial reduction in the function of these projections. The mechanisms that underlie the effects are not clear. GPR30 is a novel G-protein coupled estrogen receptor that is expressed in the brain and other tissues. Our recent studies show that GPR30 is expressed in areas of the brain important for spatial learning, memory, and attention. In addition, GPR30 in expressed by the vast majority of cholinergic neurons in the basal forebrain, and appears to be an important regulator of basal forebrain cholinergic function. We hypothesize that GPR30 plays an important role in mediating direct effects of estradiol on basal forebrain cholinergic neurons, with corresponding effects on cognitive performance. Hence, GPR30 may be an important target for developing new therapies that can enhance or restore estrogen effects on cognitive performance in older women. Here we briefly review the cholinergic hypothesis and summarize our findings to date showing effects of a GPR30 agonist and antagonist on basal forebrain cholinergic function and cognitive performance.
雌激素治疗对认知表现的有益影响随着卵巢功能丧失后时间的推移而逐渐减弱。这导致了“机会之窗”假说，即雌激素治疗必须在绝经后有限的时间内进行，才能有效。雌激素治疗对认知表现的影响至少部分归因于对支配海马体和皮质的胆碱能传入神经的影响，并且有人认为，随着年龄的增长和绝经后时间的推移，雌激素作用的丧失是由于这些投射的功能显著降低所致。其潜在机制尚不清楚。GPR30 是一种新型的 G 蛋白偶联雌激素受体，在大脑和其他组织中表达。我们最近的研究表明，GPR30 在大脑中对空间学习、记忆和注意力很重要的区域表达。此外，GPR30 表达于基底前脑的绝大多数胆碱能神经元中，并且似乎是基底前脑胆碱能功能的重要调节剂。我们假设 GPR30 在介导雌二醇对基底前脑胆碱能神经元的直接作用及其对认知表现的相应影响方面发挥着重要作用。因此，GPR30 可能是开发新疗法的重要靶点，这些新疗法可以增强或恢复老年女性雌激素对认知表现的作用。在这里，我们简要回顾了胆碱能假说，并总结了我们迄今为止的发现，这些发现表明 GPR30 激动剂和拮抗剂对基底前脑胆碱能功能和认知表现的影响。
