Orphanin FQ Suppresses NMDA Receptor-Dependent Long-Term Depression and Depotentiation in Hippocampal Dentate Gyrus

We reported previously that orphanin FQ (OFQ) inhibited NMDA receptor-mediated synaptic currents and consequently suppressed induction of long-term potentiation (LTP) in the hippocampal dentate gyrus. This study examines the effect of OFQ on several other forms of long-term synaptic plasticity in the lateral perforant path of mouse hippocampal dentate gyrus. (1) Long-term depression (LTD): a low frequency stimulation (1 Hz, 15 min) applied to the lateral perforant path induced a long-lasting reduction in the dentate field potentials in slices from 22- to 30-day-old mice. This LTD was sensitive to the NMDA receptor blocker D-AP5, and could be significantly attenuated by bath application of OFQ (1 microM, 25 min). (2) Primed LTD: induction of LTD in slices from 50- to 65-day-old mice required a priming procedure consisting of multiple high frequency stimulus trains delivered in the presence of D-AP5 before the low-frequency stimulation. OFQ applied during the low-frequency stimulation, but not during the priming trains, blocked induction of primed LTD. (3) Depotentiation: high-frequency train-induced dentate LTP could be reversed by a subsequent low-frequency stimulation. This depotentiation was also attenuated by either OFQ or D-AP5 applied during low-frequency stimulation. These results, together with our previous findings, suggest that OFQ inhibits bidirectional changes in synaptic strength in the dentate; and its multiple actions on NMDA receptor-dependent, long-term synaptic plasticity might work in tandem to regulate hippocampus-dependent learning and memory.