Akaneya Yukio, Tsumoto Tadaharu
Solution-Oriented Research for Science and Technology Program, Japan Science and Technology Agency, Suita 565-0871, Japan.
J Neurosci. 2006 Oct 4;26(40):10209-21. doi: 10.1523/JNEUROSCI.3028-06.2006.
Although prostaglandin E2 (PGE2) has a broad spectrum of biological activities that have been confirmed by previous studies, the roles of PGE2 in synaptic plasticity such as long-term potentiation (LTP) in the CNS have yet to be characterized in detail. The present results of electrophysiological and biochemical studies indicated that PGE2 is actually produced in acute visual cortex slices in response to theta-burst stimulation (TBS) and is involved postsynaptically in TBS-induced LTP. RNA interference (RNAi) for PGE2 receptor subtypes EP2 and EP3, which are known to upregulate and downregulate the level of cAMP, respectively, induced significant decreases and increases of LTP, respectively. Moreover, analysis of the localization of receptor subtypes at the membrane surface or cytosol showed that stimuli such as TBS regulate the trafficking of EP2 and EP3 between the membrane and cytosol of the postsynapses, rising up to and leaving the membrane, respectively, resulting in increased and decreased expression of EP2 and EP3 at the membrane, respectively. Increased activation of EP2 and decreased activation of EP3 by PGE2 synergistically induce an increase in cAMP level, which may induce LTP. This causes activation of CREB (cAMP response element-binding protein) in the postsynaptic cells, which may be involved in the maintenance of LTP. These observations indicate that in TBS-induced LTP of the visual cortex, PGE2 is released from the postsynaptic cells and then activates PGE2 receptors at the postsynaptic membranes, which is regulated by trafficking of the differential PGE2 receptor subtypes in an activity-dependent bidirectional manner.
尽管前列腺素E2（PGE2）具有广泛的生物学活性，这已被先前的研究所证实，但PGE2在中枢神经系统（CNS）的突触可塑性（如长时程增强，LTP）中的作用尚未得到详细表征。目前的电生理和生化研究结果表明，PGE2实际上是在急性视皮层切片中响应theta爆发刺激（TBS）而产生的，并且在突触后参与TBS诱导的LTP。已知分别上调和下调cAMP水平的PGE2受体亚型EP2和EP3的RNA干扰（RNAi）分别导致LTP显著降低和增加。此外，对受体亚型在膜表面或细胞质中的定位分析表明，诸如TBS之类的刺激调节突触后EP2和EP3在膜和细胞质之间的转运，分别上升至膜和离开膜，导致膜上EP2和EP3的表达分别增加和减少。PGE2对EP2的激活增加和对EP3的激活减少协同诱导cAMP水平升高，这可能诱导LTP。这导致突触后细胞中CREB（cAMP反应元件结合蛋白）的激活，这可能参与LTP的维持。这些观察结果表明，在视皮层的TBS诱导的LTP中，PGE2从突触后细胞释放，然后激活突触后膜上的PGE2受体，这通过不同PGE2受体亚型以活动依赖的双向方式的转运来调节。
