Sang Nan, Zhang Jian, Marcheselli Victor, Bazan Nicolas G, Chen Chu
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
J Neurosci. 2005 Oct 26;25(43):9858-70. doi: 10.1523/JNEUROSCI.2392-05.2005.
Increasing evidence suggests that cyclooxygenase-2 (COX-2) is involved in synaptic transmission and plasticity, and prostaglandin E2 (PGE2) is a key molecule in COX-2-meduated synaptic modification. However, the precise mechanisms, in particular, which subtypes of PGE2 receptors (EPs) mediate the PGE2-induced synaptic response, are not clear. Recently, we demonstrated that EPs are expressed heterogeneously in the hippocampus, and EP2/4 are mainly expressed in presynaptic terminals. Here, we report that PGE2 increased synaptic stimulus-evoked amplitudes of EPSPs in hippocampal slices and frequency of miniature EPSCs (mEPSCs) in hippocampal neurons in culture. These actions were mimicked by an EP2 agonist and attenuated by protein kinase A inhibitors. Decrease of EP2 expression through silencing the EP2 gene eliminated PGE2-induced increase of the frequency of mEPSCs. COX-2 and microsomal PGE synthase-1 (mPGES-1) and mPGES-2 are present in postsynaptic dendritic spines, because they are colocalized with PSD-95 (postsynaptic density-95), a postsynaptic marker. In addition, the frequency of mEPSCs was enhanced in neurons pretreated with interleukin-1beta or lipopolysaccharide, which elevated expression of COX-2 and mPGES-1 and produced PGE2, and this enhancement was inhibited by a COX-2 inhibitor that inhibited production of PGE2. Our results suggest that PGE2 synthesized by postsynaptically localized COX-2 functions as a retrograde messenger in hippocampal synaptic signaling via a presynaptic EP2 receptor.
越来越多的证据表明,环氧化酶-2(COX-2)参与突触传递和可塑性,前列腺素E2(PGE2)是COX-2介导的突触修饰中的关键分子。然而,确切机制,特别是哪种PGE2受体(EP)亚型介导PGE2诱导的突触反应尚不清楚。最近,我们证明EP在海马中异质性表达,且EP2/4主要表达于突触前终末。在此,我们报告PGE2增加了海马脑片突触刺激诱发的兴奋性突触后电位(EPSP)幅度以及培养的海马神经元中小兴奋性突触后电流(mEPSC)的频率。这些作用可被EP2激动剂模拟,并被蛋白激酶A抑制剂减弱。通过沉默EP2基因降低EP2表达消除了PGE2诱导的mEPSC频率增加。COX-2、微粒体PGE合酶-1(mPGES-1)和mPGES-2存在于突触后树突棘中,因为它们与突触后标记物突触后致密蛋白95(PSD-95)共定位。此外,用白细胞介素-1β或脂多糖预处理的神经元中mEPSC频率增加,这两种物质可提高COX-2和mPGES-1的表达并产生PGE2,而这种增加被抑制PGE2产生的COX-2抑制剂所抑制。我们的结果表明,由突触后定位的COX-2合成的PGE2通过突触前EP2受体在海马突触信号传导中作为逆行信使发挥作用。