Postsynaptic injection of calcium-independent phospholipase A2 inhibitors selectively increases AMPA receptor-mediated synaptic transmission.
The calcium-independent form of phospholipase A2 (iPLA2), an enzyme known to generate arachidonic acid (AA), was recently identified as the predominant constitutive phospholipase in the hippocampus. The present study shows that the iPLA2 inhibitor bromoenol lactone, when introduced into hippocampal CA1 pyramidal cells through a patch pipette, generated a dose-dependent increase in the amplitude of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs). The iPLA2 inhibitor by itself interfered with neither paired pulse facilitation nor N-methyl-D-aspartate (NMDA) receptor-mediated EPSCs, suggesting that its influence on synaptic transmission is postsynaptic in origin and specific to the AMPA subtype of glutamate receptors. Comparable results were obtained with palmitoyl trifluoromethyl ketone, a second structurally distinct iPLA2 inhibitor. The ability of iPLA2 inhibitors to increase AMPA receptor-mediated currents was also reproduced by MK-866, an inhibitor recognized to interfere with the generation of 5-lipoxygenase by-products of AA. At the biochemical level, we found that AMPA, but not NMDA glutamate receptor subunits, were upregulated in rat brain sections pre-incubated with the iPLA2 inhibitors. Collectively, these results provide the first experimental evidence that constitutive iPLA2 and/or its metabolites play an important role in the postsynaptic modulation of neurotransmission in CA1 pyramidal cells of the hippocampus.
St-Gelais
Fannie
F
Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
Ménard
Caroline
C
Congar
Patrice
P
Trudeau
Louis-Eric
LE
Massicotte
Guy
G
D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D054522:Group VI Phospholipases A2; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D066298:In Vitro Techniques; D007659:Ketones / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D017966:Pyramidal Cells / Q000187:drug effects / Q000201:enzymology*; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D007659:Ketones; D009281:Naphthalenes; D011753:Pyrones; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C109341:palmitoyl trifluoromethyl ketone; D016718:Arachidonic Acid; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; D054467:Phospholipases A2