title: mGluR5 and NMDA receptors drive the experience- and activity-dependent NMDA receptor NR2B to NR2A subunit switch.
abstract: In cerebral cortex there is a developmental switch from NR2B- to NR2A-containing NMDA receptors (NMDARs) driven by activity and sensory experience. This subunit switch alters NMDAR function, influences synaptic plasticity, and its dysregulation is associated with neurological disorders. However, the mechanisms driving the subunit switch are not known. Here, we show in hippocampal CA1 pyramidal neurons that the NR2B to NR2A switch driven acutely by activity requires activation of NMDARs and mGluR5, involves PLC, Ca(2+) release from IP(3)R-dependent stores, and PKC activity. In mGluR5 knockout mice the developmental NR2B-NR2A switch in CA1 is deficient. Moreover, in visual cortex of mGluR5 knockout mice, the NR2B-NR2A switch evoked in vivo by visual experience is absent. Thus, we establish that mGluR5 and NMDARs are required for the activity-dependent NR2B-NR2A switch and play a critical role in experience-dependent regulation of NMDAR subunit composition in vivo.
authors.affiliation: Developmental Synaptic Plasticity Section, National Institutes of Health, Bethesda, MD 20892, USA. mattaja@mail.nih.gov
authors.forename: Jose A
authors.initials: JA
authors.lastname: Matta
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ashby
authors.forename: Antonio
authors.initials: A
authors.lastname: Sanz-Clemente
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Roche
authors.forename: John T R
authors.initials: JT
authors.lastname: Isaac
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D016202:N-Methylaspartate / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014793:Visual Cortex / Q000502:physiology
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D004791:Enzyme Inhibitors; D004963:Estrenes; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010880:Piperidines; D011725:Pyridines; D011760:Pyrrolidinones; D011810:Quinoxalines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D013844:Thiazoles; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D016202:N-Methylaspartate; C010739:ifenprodil