Mitogen-Activated Protein Kinase-Mediated Reinforcement of Hippocampal Early Long-Term Depression by the Type IV-Specific Phosphodiesterase Inhibitor Rolipram and Its Effect on Synaptic Tagging-猫眼课题宝

IV型特异性磷酸二酯酶抑制剂咯利普兰促丝裂原激活蛋白激酶介导的海马早期长期抑制的强化及其对突触标记的影响

DOI：

发表时间：

2005

期刊：

Journal of Neuroscience

影响因子：

5.3

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Sheeja Navakkode;Sreedharan Sajikumar;J. Frey

罗利普兰是cAMP特异性磷酸二酯酶4（PDE 4）的选择性抑制剂，已被证明可将早期形式的长时程增强（LTP）增强为持久的LTP（晚期LTP）。此外，已经表明咯利普兰介导的LTP增强的作用与突触标记的过程相互作用（Navakkode等人，2004年）。在这里，我们表明，在CA 1海马切片从成年大鼠在体外，咯利普兰也转换一个早期形式的长期抑郁症（LTD），通常在2-3小时内衰减，一个长期持久的LTD（后期LTD），如果咯利普兰是应用在LTD诱导。罗利普兰增强LTD（RLTD）是NMDA受体和蛋白质合成依赖性的。此外，它依赖于多巴胺能D1和D5受体的协同共激活。这让我们推测，RLTD类似于电诱导的，传统的CA 1晚LTD，其特征在于异突触过程和突触标记。因此，我们问是否突触标记发生在RLTD。我们发现，早期LTD在S1突触输入转化为晚LTD，如果早期LTD被诱导在第二个独立的S2突触通路的抑制过程中的PDE咯利普兰，支持的突触标记过程中的相互作用RLTD。此外，应用特异性丝裂原活化蛋白激酶（MAPK）抑制剂PD 98059（2′-氨基-3 ′-甲氧基黄酮）或U 0126（1，4-二氨基-2，3-二氰基-1，4-双[2-氨基苯硫基]丁二烯）可预防RLTD，提示MAPK活化在RLTD中起关键作用。这种MAPK激活在RLTD期间由NMDA受体和D1和D5受体介导的Rap/B-Raf通路的协同相互作用触发，而不是由成人海马CA 1神经元中的Ras/Raf-1通路触发，如通过使用通路特异性抑制剂manumycin（Ras/Raf-1）和致死毒素82（Rap/B-Raf）所示。

Rolipram, a selective inhibitor of cAMP-specific phosphodiesterase 4 (PDE4), has been shown to reinforce an early form of long-term potentiation (LTP) to a long-lasting LTP (late LTP). Furthermore, it was shown that the effects of rolipram-mediated reinforcement of LTP interacts with processes of synaptic tagging (Navakkode et al., 2004). Here we show in CA1 hippocampal slices from adult rats in vitro that rolipram also converted an early form of long-term depression (LTD) that normally decays within 2-3 h, to a long-lasting LTD (late LTD) if rolipram was applied during LTD-induction. Rolipram-reinforced LTD (RLTD) was NMDA receptor- and protein synthesis-dependent. Furthermore, it was dependent on the synergistic coactivation of dopaminergic D1 and D5 receptors. This let us speculate that RLTD resembles electrically induced, conventional CA1 late LTD, which is characterized by heterosynaptic processes and synaptic tagging. We therefore asked whether synaptic tagging occurs during RLTD. We found that early LTD in an S1 synaptic input was transformed into late LTD if early LTD was induced in a second independent S2 synaptic pathway during the inhibition of PDE by rolipram, supporting the interaction of processes of synaptic tagging during RLTD. Furthermore, application of PD 98059 (2′-amino-3′-methoxyflavone) or U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), specific inhibitors of mitogen-activated protein kinases (MAPKs), prevented RLTD, suggesting a pivotal role of MAPK activation for RLTD. This MAPK activation was triggered during RLTD by the synergistic interaction of NMDA receptor- and D1 and D5 receptor-mediated Rap/B-Raf pathways, but not by the Ras/Raf-1 pathway in adult hippocampal CA1 neurons, as shown by the use of the pathway-specific inhibitors manumycin (Ras/Raf-1) and lethal toxin 82 (Rap/B-Raf).