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: 6.34). 01/2008; 27(50):13843-53. DOI: 10.1523/JNEUROSCI.4486-07.2007
Source: PubMed


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.

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    • "Ca 2+ influx through the NMDAR leads to CaMKII activation and recruitment to the postsynaptic density (PSD), which can be persistent and synapse specific ( Otmakhov et al., 2004; Zhang et al., 2008) (but see also ( Rose et al., 2009)). CaMKII binding to aa 1290–1309 on the NMDAR GluN2B subunit is required for this activity-dependent translocation ( Halt et al., 2012; Leonard et al., 1999; Strack & Colbran, 1998; Strack et al., 2000) and is crucial for LTP ( Barria & Malinow, 2005; Halt et al., 2012; Zhou et al., 2007). Stimulation of CaMKII results in its auto-phosphorylation on T286 causing a persistent Ca 2+-independent activation of CaMKII ( Lisman et al., 2002). "
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    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.
    Full-text · Article · Aug 2014 · F1000 Research
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    • "This is further supported by several other lines of evidence. For example, overexpressing a GluN2B carboxyl-terminal fragment (839-1482aa) that disrupts the physiological interaction between NMDAR/CaMKII leads to severe deficits in hippocampal LTP and spatial learning in transgenic mice (Zhou et al., 2007). LTP in organotypic hippocampal slices is impaired either by acute replacement of the synaptic GluN2B with GluN2A subunit that shows less binding affinity with CaMKII, or by expression of a mutant synaptic GluN2B subunit that markedly reduces the binding affinity with CaMKII (Barria and Malinow, 2005). "
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    ABSTRACT: The N-methyl-D-aspartate receptors (NMDARs) are part of a large multiprotein complex at the glutamatergic synapse. The assembly of NMDARs with synaptic proteins offers a means to regulate NMDAR channel properties and receptor trafficking, and couples NMDAR activation to distinct intracellular signaling pathways, thus contributing to the versatility of NMDAR functions. Receptor-protein interactions at the synapse provide a dynamic and powerful mechanism for regulating synaptic efficacy, but can also contribute to NMDAR overactivation-induced excitotoxicity and cellular damage under pathological conditions. An emerging concept is that by understanding the mechanisms and functions of disease-specific protein-protein interactions in the NMDAR complex, we may be able to develop novel therapies based on protein-NMDAR interactions for the treatment of brain diseases in which NMDAR dysfunction is at the root of their pathogenesis.
    Full-text · Article · Jun 2014 · Frontiers in Cellular Neuroscience
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    • "). Genetic knockout of CaMKII or disrupting CaMKII interaction with its binding proteins blunts CaMKII-dependent synaptic modification, eliminates LTP induction and impairs information processing (Barria and Malinow, 2005; Halt et al., 2012; Silva et al., 1992; Zhou et al., 2007). Thus, CaMKII is considered as a synaptic memory molecule that switches the transient calcium signal to long-lasting synaptic plasticity, and has been illustrated to play an important role in several neuropsychiatric disorders (Ly and Song, 2011; Picconi et al., 2004). "
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    ABSTRACT: Intrathecal application of α2 noradrenergic receptor agonists effectively alleviates the pathological pain induced by peripheral tissue injury. However, the spinal antinociceptive mechanisms of α2 noradrenergic receptors remain to be characterized. The present study performed immunohistochemistry and western blot to elucidate the signaling pathway initiated by α2 noradrenergic receptors in spinal dorsal horn of mice, and identified Calcium/calmodulin-dependent protein kinase II (CaMKII) as an important target for noradrenergic suppression of inflammatory pain. Our data showed that intraplantar injection of Complete Freund's Adjuvant (CFA) substantially enhanced CaMKII autophosphorylation at Threonine 286, which could be abolished by intrathecal administration of α2 noradrenergic receptor agonist clonidine. Gi protein-coupled α2 noradrenergic receptor might inhibit cAMP-dependent protein kinase (PKA) to disturb CaMKII signaling. We found that pharmacological activation of PKA in intact mice also enhanced spinal CaMKII autophosphorylation level, which was completely antagonized by clonidine. Moreover, direct PKA inhibition in CFA-injected mice mimicked the suppressive effect of α2 noradrenergic receptors on CaMKII. PKA inhibition has been shown to downregulate CaMKII by enhancing protein phosphatase activity. Consistent with this notion, spinal treatment with protein phosphatase inhibitor okadaic acid ruled out clonidine-mediated CaMKII dephosphorylation in CFA-injected mice. Through PKA/protein phosphatase/CaMKII pathway, clonidine noticeably decreased CFA-evoked phosphorylation of N-methyl-D-aspartate subtype glutamate receptor GluN1 and GluN2B subunit as well as α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid subtype glutamate receptor GluA1 subunit. These data suggested that interference with CaMKII signaling might represent an important mechanism underlying noradrenergic suppression of inflammatory pain.
    Full-text · Article · Dec 2013 · European journal of pharmacology
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