title: Orexin A induces bidirectional modulation of synaptic plasticity: Inhibiting long-term potentiation and preventing depotentiation.
abstract: The orexin system consists of two peptides, orexin A and B and two receptors, OX1R and OX2R. It is implicated in learning and memory regulation while controversy remains on its role in modulating hippocampal synaptic plasticity in vivo and in vitro. Here, we investigated effects of orexin A on two forms of synaptic plasticity, long-term potentiation (LTP) and depotentiation of field excitatory postsynaptic potentials (fEPSPs), at the Schaffer Collateral-CA1 synapse of mouse hippocampal slices. Orexin A (≧30 nM) attenuated LTP induced by theta burst stimulation (TBS) in a manner antagonized by an OX1R (SB-334867), but not OX2R (EMPA), antagonist. Conversely, at 1 pM, co-application of orexin A prevented the induction of depotentiation induced by low frequency stimulation (LFS), i.e. restoring LTP. This re-potentiation effect of sub-nanomolar orexin A occurred at LFS of 1 Hz, but not 2 Hz, and with LTP induced by either TBS or tetanic stimulation. It was significantly antagonized by SB-334867, EMPA and TCS-1102, selective OX1R, OX2R and dual OXR antagonists, respectively, and prevented by D609, SQ22536 and H89, inhibitors of phospholipase C (PLC), adenylyl cyclase (AC) and protein kinase A (PKA), respectively. LFS-induced depotentiation was antagonized by blockers of NMDA, A1-adenosine and type 1/5 metabotropic glutamate (mGlu1/5) receptors, respectively. However, orexin A (1 pM) did not affect chemical-induced depotentiation by agonists of these receptors. These results suggest that orexin A bidirectionally modulates hippocampal CA1 synaptic plasticity, inhibiting LTP via OX1Rs at moderate concentrations while inducing re-potentiation via OX1Rs and OX2Rs, possibly through PLC and AC-PKA signaling at sub-nanomolar concentrations.
authors.affiliation: Graduate Institute and College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Guan-Ling
authors.initials: GL
authors.lastname: Lu
authors.affiliation: Graduate Institute and College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia-Hsu
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Graduate Institute and College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan; Reserach Center for Chinese Medicine & Acupuncture, China Medical University, Taichung, Taiwan. Electronic address: lcchiou@ha.mc.ntu.edu.tw.
authors.forename: Lih-Chu
authors.initials: LC
authors.lastname: Chiou
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000494:pharmacology; D064446:Orexin Receptors / Q000378:metabolism; D000068797:Orexins / Q000008:administration & dosage / Q000378:metabolism*; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D046509:Tissue Culture Techniques; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C578936:Grm5 protein, mouse; C497459:Hcrtr1 protein, mouse; D018377:Neurotransmitter Agents; C497461:OX2 protein, mouse; D064446:Orexin Receptors; D000068797:Orexins; D043682:Receptor, Adenosine A1; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104077:metabotropic glutamate receptor type 1; D017868:Cyclic AMP-Dependent Protein Kinases; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases
keywords: CPA (PubChem CID: 4402); CPCCOEt (PubChem CID: 44358757); D-AP5 (PubChem CID: 135342); D609 (PubChem CID: 4234241); DHPG (PubChem CID: 108001); DPCPX (PubChem CID: 1329); Depotentiation; EMPA (PubChem CID: 9981404); H89 (PubChem CID: 5702541); Hippocampus; Long-term potentiation; NMDA (PubChem CID: 22880); Orexin; Orexin A (PubChem CID: 56842143); Orexin receptor; SB-334867 (PubChem CID: 6604926); SQ22536 (PubChem CID: 5270); Synaptic plasticity; TCS-1102 (PubChem CID: 73154080)