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-media ted synaptic currents and consequently suppressed induction of long-term po tentiation (LTP) in the hippocampal dentate gyrus. This study examines the effect of OFQ on several other forms of long-term synaptic plasticity in th e 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 fie ld potentials in slices from 22- to 30-day-old mice. This LTD was sensitive to the NMDA receptor blocker D-APS, and could be significantly attenuated by bath application of OFQ (1 mu M, 25 min). (2) Primed LTD: induction of L TD in slices from 50- to 65-day-old mice required a priming procedure consi sting of multiple high frequency stimulus trains delivered in the presence of D-APS before the low-frequency stimulation. OFQ applied during the low-f requency 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 depotent iation was also attenuated by either OFQ or D-APS applied during low-freque ncy stimulation. These results, together with our previous findings, sugges t that OFQ inhibits bidirectional changes in synaptic strength in the denta te; and its multiple actions on NMDA receptor-dependent, long-term synaptic plasticity might work in tandem to regulate hippocampus-dependent learning and memory.