title: Metaplasticity gated through differential regulation of GluN2A versus GluN2B receptors by Src family kinases.
abstract: Metaplasticity is a higher form of synaptic plasticity that is essential for learning and memory, but its molecular mechanisms remain poorly understood. Here, we report that metaplasticity of transmission at CA1 synapses in the hippocampus is mediated by Src family kinase regulation of NMDA receptors (NMDARs). We found that stimulation of G-protein-coupled receptors (GPCRs) regulated the absolute contribution of GluN2A-versus GluN2B-containing NMDARs in CA1 neurons: pituitary adenylate cyclase activating peptide 1 receptors (PAC1Rs) selectively recruited Src kinase, phosphorylated GluN2ARs, and enhanced their functional contribution; dopamine 1 receptors (D1Rs) selectively stimulated Fyn kinase, phosphorylated GluN2BRs, and enhanced these currents. Surprisingly, PAC1R lowered the threshold for long-term potentiation while long-term depression was enhanced by D1R. We conclude that metaplasticity is gated by the activity of GPCRs, which selectively target subtypes of NMDARs via Src kinases.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.forename: Catherine
authors.initials: C
authors.lastname: Trepanier
authors.forename: Bikram
authors.initials: B
authors.lastname: Sidhu
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Xie
authors.forename: Hongbin
authors.initials: H
authors.lastname: Li
authors.forename: Gang
authors.initials: G
authors.lastname: Lei
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jackson
authors.forename: John F
authors.initials: JF
authors.lastname: Macdonald
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D019061:src-Family Kinases; C121001:NR2B NMDA receptor