title: Long-term depression of NMDA receptor-mediated synaptic transmission is dependent on activation of metabotropic glutamate receptors and is altered to long-term potentiation by low intracellular calcium buffering.
abstract: Synaptic plasticity of NMDA receptor (NMDAR)-mediated transmission was investigated in the rat dentate gyrus in vitro. Isolated NMDAR EPSCs were recorded from granule cells of the dentate gyrus in response to stimulation of the medial perforant path. Long-term potentiation (LTP) or long-term depression (LTD) of NMDAR EPSCs was observed in response to brief high-frequency stimulation (HFS), with the direction and extent of plasticity dependent on the concentration and type (EGTA vs BAPTA) of the intracellular Ca2+ buffer. LTD was induced in higher concentrations of EGTA and BAPTA than LTP, and BAPTA was approximately 100-fold more potent than EGTA. Although LTD was induced in a high concentration of EGTA (10 mM), a high concentration of BAPTA (10 mM) blocked both LTP and LTD. LTP of AMPA receptor (AMPAR)-EPSCs exhibited a lower dependency on Ca2+ buffering than LTP of NMDAR EPSCs, because LTP of AMPAR EPSCs was induced by HFS in high EGTA (10 mM). We also identified a role for metabotropic glutamate receptor 5 (mGluR5) in NMDAR plasticity. HFS LTD was blocked by the group I/II mGluR antagonist LY341495 ((2S)-2-amino-2-[(1S, 2S)-2-carboxycycloprop-1-yl]-3(xanth-9-yl)propanoic acid) and by the mGluR5-selective antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). Similarly, low-frequency stimulation-induced LTD of NMDAR EPSCs was also blocked by MPEP. These findings suggest that the direction of plasticity of NMDARs is determined by the intracellular free Ca2+ concentration and is dependent on activation of mGluR5.
authors.affiliation: Department of Physiology, Trinity College, Dublin 2, Ireland.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Harney
authors.forename: Michael
authors.initials: M
authors.lastname: Rowan
authors.forename: Roger
authors.initials: R
authors.lastname: Anwyl
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002021:Buffers; D002118:Calcium / Q000502:physiology*; D018891:Dentate Gyrus / Q000166:cytology / Q000502:physiology*; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D018408:Patch-Clamp Techniques; D019580:Perforant Pathway / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D002021:Buffers; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; C114624:LY 341495; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D014966:Xanthenes; D004533:Egtazic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; C121465:6-methyl-2-(phenylethynyl)pyridine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium