Long-term potentiation in the dentate gyrus: induction and increased glutamate release are blocked by d(−)aminophosphonovalerate

Abstract

d(−)Aminophosphonovalerate, a specific antagonist of the N-methyl- d-aspartate subtype of glutamate receptor, was perfused through a push-pull cannula into the dentate gyrus of rats anaesthetized with urethan in order to observe its effect on the induction and maintenance of long-term potentiation and on the increase in release of endogenous glutamate associated with long-term potentiation. The amplitude of the population spike evoked by single test shocks to the perforant path was significantly depressed by 100 μM d(−)aminophosphonovalerate, but there was a minimal effect on the slope of the population excitatory postsynaptic potential, or on the concentration of glutamate released into the perfusate. A brief high-intensity tetanus given to the perforant path while d(−)aminophosphonovalerate was being perfused failed to induce long-term potentiation or the sustained increase in glutamate release associated with long-term potentiation. Short-term post-tetanic potentiation was not affected. After wash-out of d(−)aminophosphonovalerate, a second high-frequency train produced both long-term potentiation and an increase in glutamate release which was sustained for the subsequent l h period of observation. d(−)Aminophosphonovalerate did not suppress long-term potentiation once it had been induced. d(−)Aminophosphonovalerate (100 μM) did not itself affect in vivo release of glutamate. However, in a separate series of in vitro experiments, d(−)aminophosphonovalerate at concentrations of 50 μ M and above was found to depress the Ca 2+-dependent, K +-stimulated release of preloaded [ 14C]-glutamate from dentate slices. These results suggest that in the dentate gyrus activation of the N-methyl- d-aspartate receptor is required for the induction though not the maintenance of long-term potentiation. The possibility that presynaptic mechanisms contribute to the suppression of long-term potentiation should not be overlooked in view of our in vitro data. The further demonstration in these experiments that a high-frequency train produces a sustained increase in glutamate release only when it also produces long-term potentiation provides additional evidence for the view that the maintenance of long-term potentiation is due, at least in part, to a presynaptic mechanism.