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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
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Cerebral Cortex / cytology
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Cerebral Cortex / drug effects
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Cerebral Cortex / growth & development*
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Cerebral Cortex / physiology*
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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Gene Expression Regulation, Developmental / genetics
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Gene Expression Regulation, Developmental / physiology*
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Green Fluorescent Proteins / genetics
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Immunosuppressive Agents / pharmacology
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Mice
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Mice, Knockout
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Patch-Clamp Techniques
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Piperidines / pharmacology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, N-Methyl-D-Aspartate / deficiency
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Receptors, N-Methyl-D-Aspartate / metabolism
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Receptors, N-Methyl-D-Aspartate / physiology*
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Sirolimus / pharmacology
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Social Behavior
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Sodium Channel Blockers / pharmacology
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Tetrodotoxin / pharmacology
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Time Factors
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Valine / analogs & derivatives
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Valine / pharmacology
Substances
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Excitatory Amino Acid Antagonists
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Immunosuppressive Agents
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NR2B NMDA receptor
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Piperidines
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RNA, Small Interfering
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Receptors, N-Methyl-D-Aspartate
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Sodium Channel Blockers
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Green Fluorescent Proteins
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Tetrodotoxin
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2-amino-5-phosphopentanoic acid
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Ribosomal Protein S6 Kinases, 70-kDa
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Valine
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ifenprodil
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N-methyl D-aspartate receptor subtype 2A
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Sirolimus