Lu Guan-Ling, Lee Chia-Hsu, Chiou Lih-Chu
Graduate Institute and College of Medicine, National Taiwan University, Taipei, Taiwan.
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.
Neuropharmacology. 2016 Aug;107:168-180. doi: 10.1016/j.neuropharm.2016.03.005. Epub 2016 Mar 7.
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.
食欲素系统由两种肽（食欲素A和B）和两种受体（OX1R和OX2R）组成。它与学习和记忆调节有关，但其在体内和体外调节海马突触可塑性方面的作用仍存在争议。在此，我们研究了食欲素A对小鼠海马脑片Schaffer侧支-CA1突触处两种形式的突触可塑性的影响，即长时程增强（LTP）和场兴奋性突触后电位（fEPSP）的去增强。食欲素A（≧30 nM）以一种被OX1R拮抗剂（SB-334867）而非OX2R拮抗剂（依帕列净）拮抗的方式减弱了θ波爆发刺激（TBS）诱导的LTP。相反，在1 pM时，食欲素A的共同应用可防止低频刺激（LFS）诱导的去增强的诱导，即恢复LTP。亚纳摩尔浓度的食欲素A的这种再增强作用在1 Hz的LFS时出现，但在2 Hz时未出现，并且在TBS或强直刺激诱导的LTP时也出现。它分别被选择性OX1R、OX2R和双OXR拮抗剂SB-334867、依帕列净和TCS-1102显著拮抗，并被磷脂酶C（PLC）抑制剂D609、腺苷酸环化酶（AC）抑制剂SQ22536和蛋白激酶A（PKA）抑制剂H89所阻断。LFS诱导的去增强分别被NMDA、A1-腺苷和1/5型代谢型谷氨酸（mGlu1/5）受体的阻滞剂所拮抗。然而，食欲素A（1 pM）并不影响这些受体激动剂诱导的化学性去增强。这些结果表明，食欲素A双向调节海马CA1突触可塑性,在中等浓度时通过OX1R抑制LTP，而在亚纳摩尔浓度时可能通过PLC和AC-PKA信号传导，通过OX1R和OX2R诱导再增强。
