The excitatory amino-acid antagonist gamma-D-glutamylglycine masks rather than prevents long term potentiation of the perforant path.

The effect of the glutamate antagonist gamma-D-glutamylglycine on the induction of long-term potentiation in the dentate gyrus has been investigated in vivo. gamma-D-glutamyglycine (10(-3) M) perfused through a push-pull cannula into the dentate gyrus, rapidly reduced perforant path evoked potentials. Application to the perforant path of a high-frequency train (250 Hz, 500 ms), which in control animals reliably produced long term potentiation, had no effect on the evoked potentials when applied during blockade by gamma-D-glutamylglycine. This result was obtained despite the inability of gamma-D-glutamylglycine completely to inhibit the evoked potentials. However, when standard medium was reintroduced, potentiation was revealed in animals that had received the high-frequency train, whereas in animals that had received no high-frequency train during gamma-D-glutamylglycine inhibition the potentials returned only to pre-drug levels. In additional experiments, in which the dentate gyrus was continuously perfused with [3H]glutamine, and the steady state outflow of [3H]glutamate was measured, it was observed that gamma-D-glutamylglycine (10(-3) M) increased the steady state release of [3H]glutamate into the perfusate. From this result it is likely that gamma-D-glutamylglycine does not have any presynaptic inhibitory activity at the perforant path-granule cell synapse. The results indicate that a high frequency train applied to the perforant path during a period of inhibition by gamma-D-glutamylglycine was able to induce long term potentiation, whose expression was, however, masked until the glutamate antagonist was removed.(ABSTRACT TRUNCATED AT 250 WORDS)