A critical role for GluN2B-containing NMDA receptors in cortical development and function

Neuron. 2011 Dec 8;72(5):789-805. doi: 10.1016/j.neuron.2011.09.023.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / growth & development*
  • Cerebral Cortex / physiology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Green Fluorescent Proteins / genetics
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Mice, Knockout
  • Patch-Clamp Techniques
  • Piperidines / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, N-Methyl-D-Aspartate / deficiency
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Sirolimus / pharmacology
  • Social Behavior
  • Sodium Channel Blockers / pharmacology
  • Tetrodotoxin / pharmacology
  • Time Factors
  • Valine / analogs & derivatives
  • Valine / pharmacology


  • Excitatory Amino Acid Antagonists
  • Immunosuppressive Agents
  • NR2B NMDA receptor
  • Piperidines
  • RNA, Small Interfering
  • Receptors, N-Methyl-D-Aspartate
  • Sodium Channel Blockers
  • Green Fluorescent Proteins
  • Tetrodotoxin
  • 2-amino-5-phosphopentanoic acid
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Valine
  • ifenprodil
  • N-methyl D-aspartate receptor subtype 2A
  • Sirolimus