title: A critical role for GluN2B-containing NMDA receptors in cortical development and function.
abstract: The subunit composition of N-methyl D-aspartate receptors (NMDARs) is tightly regulated during cortical development. NMDARs are initially dominated by GluN2B (NR2B), whereas GluN2A (NR2A) incorporation increases after birth. The function of GluN2B-containing NMDARs during development, however, is incompletely understood. We generated a mouse in which we genetically replaced GluN2B with GluN2A (2B→2A). Although this manipulation restored NMDAR-mediated currents at glutamatergic synapses, it did not rescue GluN2B loss of function. Protein translation-dependent homeostatic synaptic plasticity is occluded in the absence of GluN2B, and AMPA receptor contribution is enriched at excitatory cortical synapses. Our experiments indicate that specificity of GluN2B-mediated signaling is due to its unique interaction with the protein effector alpha calcium-calmodulin kinase II and the regulation of the mTOR pathway. Homozygous 2B→2A mice exhibited high rates of lethality, suppressed feeding, and depressed social exploratory behavior. These experiments indicate that GluN2B-containing NMDARs activate unique cellular processes that cannot be rescued by replacement with GluN2A.
authors.affiliation: Tulane University Neuroscience Program, 2013 Percival Stern Hall, 6400 Freret Street, New Orleans, LA 70118, USA.
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Wang
authors.forename: Richard G
authors.initials: RG
authors.lastname: Held
authors.forename: Shiao-Chi
authors.initials: SC
authors.lastname: Chang
authors.forename: Lingling
authors.initials: L
authors.lastname: Yang
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
authors.forename: Anirvan
authors.initials: A
authors.lastname: Ghosh
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Hall
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D012919:Social Behavior; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018691:Excitatory Amino Acid Antagonists; D049452:Green Fluorescent Proteins; D007166:Immunosuppressive Agents; D010880:Piperidines; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D014633:Valine; C121001:NR2B NMDA receptor; C056639:2-amino-5-phosphopentanoic acid; C010739:ifenprodil