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

CC Wang, RG Held, SC Chang, L Yang, E Delpire… - neuron, 2011 - cell.com
CC Wang, RG Held, SC Chang, L Yang, E Delpire, A Ghosh, BJ Hall
neuron, 2011cell.com
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 …
Summary
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.
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