Using intracellular and extracellular recordings in rat hippocampal slices, we have investigated the interactions between the quisqualate metabotropic receptor (QP) and currents mediated by N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). We found that trans- (t)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) and 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) potentiated NMDA but not AMPA-mediated currents. Intracellular injections of selective protein kinase C inhibitors prevented the up-regulation of the NMDA response. The physiological consequence of the up-regulation by ACPD of the NMDA response on the threshold of long-term potentiation induction was tested. We found that a subthreshold train of electrical stimulation that produced short-term potentiation generated long-term potentiation when coupled with ACPD application, an effect which was not produced by AMPA or NMDA. This effect was blocked by an inhibitor of protein kinase C. These results demonstrate for the first time that one subtype of glutamate receptor (QP) can regulate another subtype of glutamate receptor (NMDA) through the activation of protein kinase C. Our results also suggest that the NMDA receptor is regulated by protein kinase C, and that the intracellular level of protein kinase C may determine the threshold for induction of long-term potentiation.