title: Plasticity of synaptic GluN receptors is required for the Src-dependent induction of long-term potentiation at CA3-CA1 synapses.
abstract: The induction of long-term potentiation (LTP) of CA3-CA1 synapses requires activation of postsynaptic N-methyl-D-aspartate receptors (GluNRs). At resting potential, the contribution of GluNRs is limited by their voltage-dependent block by extracellular Mg(2+). High-frequency afferent stimulation is required to cause sufficient summation of excitatory synaptic potentials (EPSPs) to relieve this block and to permit an influx of Ca(2+). It has been assumed that this relief of Mg(2+) block is sufficient for induction. We postulated that the induction of LTP also requires a Src-dependent plasticity of GluNRs. Using whole-cell recordings, LTP (GluARs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors-EPSCS was induced by pairing postsynaptic depolarization with presynaptic stimulation. This LTP was both GluNR and Src-dependent, being sensitive to AP-5, a GluNR selective antagonist, or to SU6656, a Src-selective inhibitor. When CNQX was used to block all GluARs, we observed a long-lasting potentiation of GluNR-mediated EPSCs. This plasticity was prevented by transiently blocking GluNRs during the induction protocol or by chelating intracellular Ca(2+). GluNRs plasticity was also prevented by bath applications of SU6656 or intracellular applications of the Src-selective inhibitory peptide, Src(40-58). It was also blocked by preventing activation of protein kinase C, a kinase that is upstream of Src-kinase-dependent regulation of GluNRs. Both GluN2A and GluN2B receptors were found to contribute to the plasticity of GluNRs. The contribution of GluNRs and, in particular, their plasticity to the maintenance of LTP was explored using AP5 and SU6656, respectively. When applied >20 min after induction neither drug influenced the magnitude of LTP. However, when applied immediately after induction, treatment with either drug caused the initial magnitude of LTP to progressively decrease to a sustained phase of reduced amplitude. Collectively, our findings suggest that GluNR plasticity, although not strictly required for induction, is necessary for the maintenance of a nondecrementing component of LTP.
authors.affiliation: Department of Physiology and Pharmacology, Robarts Research Institute, University of Western Ontario, London, Ontario.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Li
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jackson
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.forename: Catherine
authors.initials: C
authors.lastname: Trepanier
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
authors.forename: John F
authors.initials: JF
authors.lastname: Macdonald
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018690:Excitatory Amino Acid Agonists; D007211:Indoles; D016194:Receptors, N-Methyl-D-Aspartate; D017661:Receptors, Presynaptic; C416927:SU 6656; D013449:Sulfonamides; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D019061:src-Family Kinases