BIDIRECTIONAL MODULATION OF AMPA RECEPTOR PROPERTIES BY EXOGENOUS PHOSPHOLIPASE A(2) IN THE HIPPOCAMPUS

The synaptic modifications underlying long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission in various brain structures may result from changes in the properties of the alpha-amin o-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamat e receptors. In the present study, we report that treatment of rat syn aptoneurosomes with increasing concentrations of phospholipase A(2) (P LA(2)) produces a biphasic effect on AMPA receptor binding, with low c oncentrations causing a decrease and high concentrations an increase i n agonist binding. Analysis of the saturation kinetics of H-3-AMPA bin ding revealed that the biphasic effect of PLA(2) was due to modificati ons in receptor affinity and not to changes in the maximum number of b inding sites for AMPA receptors. The 12-lipoxygenase inhibitors prefer entially reduced PLA(2)-induced decrease in AMPA binding and treatment of hippocampal synaptoneurosomes with arachidonic acid (AA) or 12-HPE TE, the first metabolite generated from the hydrolysis of AA by 12-lip oxygenases, decreased H-3-AMPA binding. Moreover, electrophysiological experiments indicated that the 12-lipoxygenase inhibitor baicalein to tally blocked LTD formation in area CA(1) of hippocampal slices. The d ecrease in H-3-AMPA binding elicited by low concentrations of PLA(2), as well as the level of LTD, were partially reduced by AA-861, a 5-lip oxygenase inhibitor, while the cyclooxygenase inhibitor indomethacin d id not prevent LTD formation or the effects of PLA(2) on H-3-AMPA bind ing. Our results provide evidence for a possible involvement of lipoxy genase metabolites in the regulation of AMPA receptor during synaptic depression. In addition, they strongly support the idea that the same biochemical pathway, i.e., NMDA receptor activation and endogenous PLA (2) stimulation, may represent a common mechanism resulting in AMPA re ceptor alterations for both LTP and LTD formation. Hippocampus 1998;8: 299-309. (C) 1998 Wiley-Liss, Inc.