The NMDA receptor is crucial for the induction of neuronal plasticity throughout the central nervous system. Although traditionally thought of as relatively stable compared to AMPA receptors, recent evidence suggests that synaptic NMDA receptors are in fact quite labile. In this study, the NMDA receptor-mediated synaptic responses of two pathways onto CA1 neurones were studied. Stimulating electrodes were placed in the stratum radiatum (SR) and stratum lacunosum moleculare (SLM) to stimulate the Schaffer collateral (SC) and temporoammonic pathways (TA) of the hippocampus, respectively. Whole-cell voltage-clamp recordings were obtained from CA 1 principal neurones. Each pathway was alternately stimulated and pharmacologically isolated NMDAR-mediated EPSCs were recorded. Application of the group I mGlu receptor agonist DHPG caused L TD of NMDA receptor-mediated responses of the SC, but not the TA pathway. DHPG-L TDNMDA did not appear to influence the postsynaptic NMDA receptor subunit composition as assessed by the decay time constant of the NMDA receptor-mediated EPSC and the efficacy of R025-6981, an antagonist of GluN2B-containing NMDA receptors. Also, a 5 Hz 20-second stimulation protocol was again shown to evoke L TD of NMDA receptor-mediated responses of the SC, but not the TA pathway. This 'theta frequency-evoked' L TD was also mediated by mGlu receptors but, in contrast to DHPG-L TDNMDA, did cause a change in the decay time constant of the NMDA- receptor mediated EPSC. 5 Hz 20 seconds stimulation did not cause L TD of AMPA receptor-mediated transmission but induced metaplasticity in extracellular field recordings, as it inhibited the subsequent induction of L TP of field EPSPs. These results demonstrate two forms of plasticity that are both expressed at one synapse of CA1 principal neurones but not another. The downregulation of NMDA receptor-mediated transmission in this manner may have functional consequences for synaptic transmission and plasticity within the hippocampus. 2