The Neuropeptide Nociceptin Is a Synaptically Released Endogenous Inhibitor of Hippocampal Long-Term Potentiation

Abstract

Hippocampal long-term potentiation (LTP) of excitatory synaptic transmission has been regarded as a cellular model of learning and memory. Its induction is regulated by many functional molecules at synapses, including the neuropeptide nociceptin, which is identified as an endogenous ligand for the orphan opioid receptor. Mutant mice lacking the receptor exhibit enhanced LTP and hippocampusdependent memory formation; however, the precise molecular and cellular mechanism is largely unknown. Here, we show that LTP in the hippocampal CA1 region is inhibited by nociceptin synaptically released from interneurons by tetanic stimulation. This endogenous nociceptin downregulates the excitability of pyramidal cells by the hyperpolarization induced by the activation of K ϩ channels, which are the common target shared with GABA B receptors, although the mode of action is considerably different. Interestingly, the modulation of LTP by endogenous nociceptin is not observed when theta-burst stimulation is used instead of tetanic stimulation, suggesting that relatively longer high-frequency synaptic activation is required for the release of endogenous nociceptin. These results indicate that, in addition to GABA, nociceptin released from interneurons by their high-frequency activation is a novel endogenous neuromodulator that negatively regulates LTP induction in the hippocampus through direct modulation of pyramidal cells.

Nociceptin Receptor Impairs Recognition Memory via Interaction with NMDA Receptor-Dependent Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling in the Hippocampus

“…This modulation is in part mediated by antagonism of glutamatergic function at the NMDA receptor. The lack of effect of NOP receptor activation on basal pERK level further suggests that N/OFQ modulatory role is activitydependent as recently demonstrated by electrophysiological approaches (Manabe et al, 1998;Bongsebandhu-phubhakdi and Manabe, 2007).…”

“…NOP receptors are also located on interneurons and pyramidal cells throughout the hippocampus (Houtani et al, 2000), and can therefore directly modulate NMDA receptor function at the postsynaptic level. Consistent with this view, electrophysiological studies showed that exogenous as well as endogenous N/OFQ potently inhibits NMDA receptor-dependent long-term potentiation through direct action on pyramidal and granule cells in the hippocampus (Yu and Xie, 1998;Bongsebandhu-phubhakdi and Manabe, 2007). NOP receptor is a G-protein-coupled receptor that negatively regulates the activity of adenylate cyclases, inhibits voltage-gated Ca 2ϩ channels and activates inward rectifying K ϩ channels.…”

“…Furthermore, NOP receptor activation with N/OFQ or synthetic agonists impairs memory performances in a variety of cognitive tasks in rodents (Sandin et al, 1997;Hiramatsu and Inoue, 1999;Redrobe et al, 2000;Higgins et al, 2002;Mamiya et al, 2003;Liu et al, 2007;Roozendaal et al, 2007), whereas the deletion of NOP receptor or preproN/OFQ gene produces the opposite effects (Manabe et al, 1998;Higgins et al, 2002;Mamiya et al, 2003). Consistent with these findings, electrophysiological studies showed that N/OFQ potently inhibits synaptic transmission and synaptic plasticity in the hippocampus and the amygdala (Yu et al, 1997;Meis and Pape, 1998;Yu and Xie, 1998;Wei and Xie, 1999; Bongsebandhu-phubhakdi and Manabe, 2007).…”

“…Electrophysiological studies indicate that N/OFQ inhibits synaptic transmission and plasticity in the hippocampus through suppression of glutamatergic function at the NMDA receptor (Manabe et al, 1998;Yu and Xie, 1998;Wei and Xie, 1999;Bongsebandhu-phubhakdi and Manabe, 2007). Based on these findings, we hypothesized that NOP receptors may regulate recognition memory by interacting with NMDA receptor signaling in the hippocampus.…”

Kinase-Dead Knock-In Mouse Reveals an Essential Role of Kinase Activity of Ca2+/Calmodulin-Dependent Protein Kinase II in Dendritic Spine Enlargement, Long-Term Potentiation, and Learning

“…Standard procedures were used to prepare hippocampal slices (400 m thick) from male mice aged 7-10 weeks (Bongsebandhu-phubhakdi and Manabe, 2007). External solution contained the following (in mM): 119 NaCl, 2.5 KCl, 1.3 MgSO 4 , 2.5 CaCl 2 , 1.0 NaH 2 PO 4 , 26.2 NaHCO 3 , 11 glucose, and 0.1 picrotoxin (a GABA A receptor antagonist).…”