Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning

J Neurosci. 2007 Dec 12;27(50):13843-53. doi: 10.1523/JNEUROSCI.4486-07.2007.

Abstract

The NR2B subunit of the NMDA receptor interacts with several prominent proteins in the postsynaptic density, including calcium/calmodulin-dependent protein kinase II (CaMKII). To determine the function of these interactions, we derived transgenic mice expressing a ligand-activated carboxy-terminal NR2B fragment (cNR2B) by fusing this fragment to a tamoxifen (TAM)-dependent mutant of the estrogen receptor ligand-binding domain LBD(G521R). Here, we show that induction by TAM allows the transgenic cNR2B fragment to bind to endogenous CaMKII in neurons. Activation of the LBD(G521R)-cNR2B transgenic protein in mice leads to the disruption of CaMKII/NR2B interactions at synapses. The disruption decreases Thr286 phosphorylation of alphaCaMKII, lowers phosphorylation of a key CaMKII substrate in the postsynaptic membrane (AMPA receptor subunit glutamate receptor 1), and produces deficits in hippocampal long-term potentiation and spatial learning. Together our results demonstrate the importance of interactions between CaMKII and NR2B for CaMKII activity, synaptic plasticity, and learning.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Ligands
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology
  • Maze Learning / drug effects
  • Maze Learning / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuronal Plasticity / physiology*
  • Neurons / drug effects
  • Neurons / physiology
  • Organ Culture Techniques
  • Phosphorylation
  • Receptors, Estrogen / genetics
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Synapses / physiology*
  • Tamoxifen / pharmacology

Substances

  • Ligands
  • NR2B NMDA receptor
  • Receptors, Estrogen
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Fusion Proteins
  • Tamoxifen
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2