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The Journal of Neuroscience, December 12, 2007, 27(50):13843-13853; doi:10.1523/JNEUROSCI.4486-07.2007

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Behavioral/Systems/Cognitive
Interactions between the NR2B Receptor and CaMKII Modulate Synaptic Plasticity and Spatial Learning

Yu Zhou,^1,2,3,4 Eiki Takahashi,^1,2,3,4 Weidong Li,^1,2,3,4 Amy Halt,⁶ Brian Wiltgen,^1,2,3,4 Dan Ehninger,^1,2,3,4 Guo-Dong Li,⁵ Johannes W. Hell,⁶ Mary B. Kennedy,⁷ and Alcino J. Silva^1,2,3,4

¹Department of Neurobiology, ²Semel Institute, ³Department of Psychology, ⁴Brain Research Institute, and ⁵Department of Molecular and Medical Pharmacology, Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095-1761, ⁶Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242-1109, and ⁷Division of Biology 216-76, California Institute of Technology, Pasadena, California 91125

Correspondence should be addressed to Alcino J. Silva, Department of Neurobiology, University of California, Los Angeles, Los Angeles, California 90095-1761. Email: silvaa{at}mednet.ucla.edu

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 CaMKII, 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.

Key words: CaMKII; NMDA receptor; synapse; plasticity; learning; memory

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Received July 30, 2007; revised Oct. 25, 2007; accepted Oct. 25, 2007.

Correspondence should be addressed to Alcino J. Silva, Department of Neurobiology, University of California, Los Angeles, Los Angeles, California 90095-1761. Email: silvaa{at}mednet.ucla.edu

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