A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro
A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro
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DOI：
10.1016/s0028-3908(02)00375-1
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发表时间：
2003-03-01
影响因子：
4.7
通讯作者：
O'Connor, JJ
中科院分区：
文献类型：
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作者：
Murray, HJ;O'Connor, JJ
长期增强（LTP）和长期抑制（LTD）是活动依赖性突触可塑性的两种形式，被认为与学习和记忆有关。有证据表明，环氧化酶-2 （COX-2）是一种将花生四烯酸转化为前列腺素的酶，在突触后树突棘中表达，并受突触活性的调节。COX-2抑制已被证明可直接减弱海马齿状回的LTP。最近，p38 MAP激酶级联（细胞用于COX-2表达的途径）也被认为与海马CA1区域的LTD诱导有关。本研究首次证实了COX-2和p38 MAP激酶在LTD中的直接作用，并证实了COX-2在大鼠齿状回中对UP的抑制作用。破伤风刺激前60分钟灌注COX-2抑制剂NS-398 （1 μ m）导致LTD衰减（84 +/- 5%,n = 5，对照组为57 +/- 7%，n = 6, P < 0.05）。长时间暴露于NS-398 （1 muM) 2小时导致UP显著降低（71 +/- 8%,n = 5, P < 0.01），而对照组在HFS后60分钟为170 +/- 11%，n = 5）。p38 MAPK抑制剂SB220025 （250 nM）显著降低LTD (88 %, n 7；与60 min时的对照相比，P < 0.01, 56 %, n = 6)，但对LTP无显著影响。NS-398和SB220025对分离的nmda介导的EPSP无显著影响。这些数据表明，COX-2和p38 MAPK在体外齿状回LTD中具有独立于NMDA受体激活的作用。2003爱思唯尔科学有限公司版权所有。
Long-term potentiation (LTP) and long-term depression (LTD) are two forms of activity-dependent synaptic plasticity that are thought to be involved in learning and memory. Evidence has shown that cyclooxygenase-2 (COX-2), an enzyme that converts arachidonic acid to prostaglandins, is expressed in postsynaptic dendritic spines and is regulated by synaptic activity. COX-2 inhibition has been shown to directly attenuate LTP in the dentate gyrus of the hippocampus. Also recently the p38 MAP kinase cascade, a pathway utilised by cells for COX-2 expression, has been implicated in LTD induction in the CA1 region of the hippocampus. Here we demonstrate for the first time a direct role for COX-2 and p38 MAP kinase in LTD and confirm the inhibitory role of COX-2 in UP in the rat dentate gyrus. Perfusion of the COX-2 inhibitor NS-398 (1 muM) 60 min before tetanic stimulation resulted in an attenuation of LTD (84 +/- 5%, n = 5 compared to controls of 57 +/- 7%, n = 6, P < 0.05). Prolonged exposure (2 h) to NS-398 (1 muM) resulted in a significant reduction in UP (71 +/- 8%, n = 5, P < 0.01 compared to controls of 170 +/- 11%, n = 5 at 60 min post HFS). The p38 MAPK inhibitor, SB220025 (250 nM) significantly attenuated LTD (88 5%, n 7; P < 0.01 compared to vehicle controls at 60 min, 56 5%, n = 6) but had no significant effect on LTP. Both NS-398 and SB220025 had no significant effect on the isolated NMDA-mediated EPSP. These data demonstrate a role for COX-2 and p38 MAPK in LTD in the dentate gyrus in vitro that is independent of NMDA receptor activation. (C) 2003 Elsevier Science Ltd. All rights reserved.