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

Department of Neurobiology, Semel Institute, Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095-1761, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 01/2008; 27(50):13843-53. DOI: 10.1523/JNEUROSCI.4486-07.2007
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Learning can involve formation of new synapses and loss of synapses, providing memory traces of learned skills. Recent findings suggest that these synapse rearrangements reflect assembly of task-related sub-circuits from initially broadly distributed and sparse connectivity in the brain. These local circuit remodeling processes involve rapid emergence of synapses upon learning, followed by protracted validation involving strengthening of some new synapses, and selective elimination of others. The timing of these consolidation processes can vary. Here, we review these findings, focusing on how molecular/cellular mechanisms of synapse assembly, strengthening, and elimination might interface with circuit/system mechanisms of learning and memory consolidation. An integrated understanding of these learning-related processes should provide a better basis to elucidate how experience, genetic background, and disease influence brain function.
    Trends in Neurosciences 09/2014; 37(10). DOI:10.1016/j.tins.2014.08.011 · 12.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A synaptic protein, Ca(2+)/Calmodulin dependent protein kinase II (CaMKII), has complex state transitions and facilitates the emergence of long term potentiation (LTP), which is highly correlated to memory formation. Two of the state transitions are critical for LTP: (1) threonine 286 autophosphorylation of CaMKII; and (2) binding to N-methyl-d-aspartate receptor (NMDAR) in the postsynaptic density (PSD) to form CaMKII-NMDAR complex. Both of these state transitions retain the activity of CaMKII when the induction signal disappears which is very important for the long-lasting characteristics of LTP. However, the possible relationships between the state transitions in the emergence of LTP are not well understood. We develop a mathematical model of the formation of CaMKII-NMDAR complex with the full state transitions of CaMKII, including the autophosphorylation, based on ordinary differential equations. In addition, we formulate a probabilistic framework for the binding between CaMKII and NMDAR. The model gives accurate predictions of the behaviours of CaMKII in comparisons to the experimental observations. Using the model, we show that: (1) the formation of CaMKII-NMDAR complex is dependent not only on the binding affinity between CaMKII and NMDAR, but also on the translocation of CaMKII into PSD; and (2) the autophosphorylation is not a requirement for the formation of CaMKII-NMDAR complex, but is important for the rapid formation of CaMKII-NMDAR complex during LTP. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Journal of Theoretical Biology 11/2014; 365C:403-419. DOI:10.1016/j.jtbi.2014.11.001 · 2.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Learning and memory as well as long-term potentiation (LTP) depend on Ca (2+) influx through the NMDA-type glutamate receptor (NMDAR) and the resulting activation of the Ca (2+) and calmodulin-dependent protein kinase (CaMKII). Ca (2+) influx via the NMDAR triggers CaMKII binding to the NMDAR for enhanced CaMKII accumulation at post-synaptic sites that experience heightened activity as occurring during LTP. Previously, we generated knock-in (KI) mice in which we replaced two residues in the NMDAR GluN2B subunit to impair CaMKII binding to GluN2B. Various forms of LTP at the Schaffer collateral synapses in CA1 are reduced by 50%. Nevertheless, working memory in the win-shift 8 arm maze and learning of the Morris water maze (MWM) task was normal in the KI mice although recall of the task was impaired in these mice during the period of early memory consolidation. We now show that massed training in the MWM task within a single day resulted in impaired learning. However, learning and recall of the Barnes maze task and contextual fear conditioning over one or multiple days were surprisingly unaffected. The differences observed in the MWM compared to the Barnes maze and contextual fear conditioning suggest a differential involvement of CaMKII and the specific interaction with GluN2B, probably depending on varying degrees of stress, cognitive demand or even potentially different plasticity mechanisms associated with the diverse tasks.
    01/2014; 3:193. DOI:10.12688/f1000research.4660.1