A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro

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.