Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning.
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.
Zhou
Yu
Y
Department of Neurobiology, Semel Institute, Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095-1761, USA.
Takahashi
Eiki
E
Li
Weidong
W
Halt
Amy
A
Wiltgen
Brian
B
Ehninger
Dan
D
Li
Guo-Dong
GD
Hell
Johannes W
JW
Kennedy
Mary B
MB
Silva
Alcino J
AJ
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D008024:Ligands; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D010766:Phosphorylation; D011960:Receptors, Estrogen / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology
D008024:Ligands; C121001:NR2B NMDA receptor; D011960:Receptors, Estrogen; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2