Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity.
The functional significance of cyclooxygenases (COX-1 and -2), the key enzymes that convert arachidonic acid (AA) to prostaglandins (PGs) in brain, is unclear, although they have been implicated in cellular functions and in some neurologic disorders, including stroke, epilepsy, and Alzheimer's disease. Recent evidence that COX-2 is expressed in postsynaptic dendritic spines (which are specialized structures involved in synaptic signaling) and is regulated by synaptic activity implies participation of COX-2 in neuronal plasticity. However, direct evidence is lacking. Here we demonstrate that selective COX-2 inhibitors significantly reduced postsynaptic membrane excitability, back-propagating dendritic action potential-associated Ca2+ influx, and long-term potentiation (LTP) induction in hippocampal dentate granule neurons, while a COX-1 inhibitor is ineffective. All of these actions were effectively reversed by exogenous application of PGE2 but not of PGD2 or PGF(2alpha). Our results indicate that COX-2-generated PGE2 regulates membrane excitability and long-term synaptic plasticity in hippocampal perforant path-dentate gyrus synapses.
Chen
Chu
C
Neuroscience Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA. cchen@lsuhsc.edu
Magee
Jeffery C
JC
Bazan
Nicolas G
NG
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003712:Dendrites / Q000201:enzymology; D018891:Dentate Gyrus / Q000201:enzymology*; D015232:Dinoprostone / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology*; D009578:Nitrobenzenes / Q000494:pharmacology; D009924:Organ Culture Techniques; D019580:Perforant Pathway / Q000201:enzymology; D017729:Presynaptic Terminals / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013569:Synapses / Q000201:enzymology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone; C012655:nimesulide