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 LTP in the rat dentate gyrus. Perfusion of the COX-2 inhibitor NS-398 (1 micro M) 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 micro M) resulted in a significant reduction in LTP (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.
Murray
H J
HJ
Department of Human Anatomy and Physiology, Conway Institute of Biomolecular and Biomedical Research, National Neuroscience Network, University College Dublin, Earlsfort Terrace, 2, Dublin, Ireland.
O'Connor
J J
JJ
D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004594:Electrophysiology / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D007527:Isoenzymes; D009578:Nitrobenzenes; D011743:Pyrimidines; D011810:Quinoxalines; C110631:SB 220025; D013449:Sulfonamides; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases