Interactions between the NR2B Receptor and CaMKII Modulate Synaptic Plasticity and Spatial Learning

Zhou, Yu; Takahashi, Eiki; Li, Weidong; Halt, Amy R; Wiltgen, Brian J.; Ehninger, Dan; Li, Guo Dong; Hell, Johannes; Kennedy, Mary B.; Silva, Alcino J.

doi:10.1523/jneurosci.4486-07.2007

Cited by 159 publications

(150 citation statements)

References 56 publications

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“…Those two modes of CaMKII autonomous activity, T286 autophosphorylation and GluN2B binding, could thus have distinct terms and serve different functions inside the spine. The importance of GluN2B NMDAR subunit interaction with ␣CaMKII in synaptic potentiation has been already demonstrated (Barria and Malinow, 2005;Zhou et al, 2007). The functional link between CaMKII and ERK signaling in LTP was suggested by Zhu et al (2002), who showed that the MEK inhibitor PD98095 could affect CaMKII-mediated increase in synaptic insertion of AMPARs.…”

Section: Discussionmentioning

confidence: 90%

Interaction Between CaMKII and GluN2B Controls ERK-Dependent Plasticity

Gaamouch

Buisson²,

Moustié³

et al. 2012

Journal of Neuroscience

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Understanding how brief synaptic events can lead to sustained changes in synaptic structure and strength is a necessary step in solving the rules governing learning and memory. Activation of ERK1/2 (extracellular signal regulated protein kinase 1/2) plays a key role in the control of functional and structural synaptic plasticity. One of the triggering events that activates ERK1/2 cascade is an NMDA receptor (NMDAR)-dependent rise in free intracellular Ca 2ϩ concentration. However the mechanism by which a short-lasting rise in Ca 2ϩ concentration is transduced into long-lasting ERK1/2-dependent plasticity remains unknown. Here we demonstrate that although synaptic activation in mouse cultured cortical neurons induces intracellular Ca 2ϩ elevation via both GluN2A and GluN2B-containing NMDARs, only GluN2B-containing NMDAR activation leads to a long-lasting ERK1/2 phosphorylation. We show that ␣CaMKII, but not ␤CaMKII, is critically involved in this GluN2B-dependent activation of ERK1/2 signaling, through a direct interaction between GluN2B and ␣CaMKII. We then show that interfering with GluN2B/␣CaMKII interaction prevents synaptic activity from inducing ERKdependent increases in synaptic AMPA receptors and spine volume. Thus, in a developing circuit model, the brief activity of synaptic GluN2B-containing receptors and the interaction between GluN2B and ␣CaMKII have a role in long-term plasticity via the control of ERK1/2 signaling. Our findings suggest that the roles that these major molecular elements have in learning and memory may operate through a common pathway.

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Section: Discussionmentioning

confidence: 90%

Interaction Between CaMKII and GluN2B Controls ERK-Dependent Plasticity

Gaamouch

Buisson²,

Moustié³

et al. 2012

Journal of Neuroscience

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“…It has been shown that binding of CaMKII to the NR2B subunit is necessary for LTP induction (Barria and Malinow, 2005). More recently, inducible and reversible disruption of NR2B/CaMKII interactions in transgenic mice has been shown to be involved in downregulation of ␣CaMKII autophosphorylation and reduction of LTP in the hippocampus (Zhou et al, 2007). Our data are in agreement with all these previous observations: here, we show that CaMKII inhibition by means of Ant-AIP-2 leads to a disruption of ␣CaMKII/ NR2B complex and to a subsequent reduction of ␣CaMKII and NR2B protein levels at synapses without affecting NR2A subunit localization, and that this molecular event is associated with a decreased LTP induction.…”

Section: Discussionmentioning

confidence: 99%

“…Even if the molecular details of these interactions have been addressed, the physiological function of these interactions still remains to be clarified. Interestingly, recent data have put forward new roles for NMDA receptor-CaMKII complex in synaptic plasticity (Barria and Malinow, 2005;Zhou et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Decreased NR2B Subunit Synaptic Levels Cause Impaired Long-Term Potentiation But Not Long-Term Depression

Gardoni¹,

Mauceri

Malinverno³

et al. 2009

J. Neurosci.

128

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The discovery of the molecular mechanisms regulating the abundance of synaptic NMDA receptors is essential for understanding how synaptic plasticity, as well as excitotoxic events, are regulated. However, a complete understanding of the precise molecular mechanisms regulating the composition of the NMDA receptor complex at hippocampal synapse is still missing. Here, we show that 2 h of CaMKII inhibition leads to a specific reduction of synaptic NR2B-containing NMDA receptors without affecting localization of the NR2A subunit; this molecular event is accompanied by a dramatic reduction in the induction of long-term potentiation (LTP), while long-term depression induction is unaffected. The same molecular and functional results were obtained by disrupting NR2B/PSD-95 complex with NR2B C-tail cell permeable peptide (TAT-2B). These data indicate that NR2B redistribution between synaptic and extrasynaptic membranes represents an important molecular disturbance of the glutamatergic synapse and affects the correct induction of LTP.

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“…Downstream of NMDARs, CaMKII binding to the NMDAR subunit, GluN2B, has been shown to be important for induction and maintenance of LTP (Lisman et al, 2002;Barria and Malinow, 2005;Zhou et al, 2007;Sanhueza et al, 2011) and activitydependent new spine outgrowth (Hamilton et al, 2012); interruption of this interaction causes decreased spine density (Gambrill and Barria, 2011). Moreover, CaMKII activation is important for new spine stabilization during experiencedependent plasticity (Wilbrecht et al, 2010).…”

Section: Nmdar Activation and Interaction Of Nmdars With Camkii Are Rmentioning

confidence: 99%

LTP-Induced Long-Term Stabilization of Individual Nascent Dendritic Spines

2013

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Learning new tasks has been associated with increased growth and stabilization of new dendritic spines. We examined whether long-term potentiation (LTP), a key cellular mechanism thought to underlie learning, plays a role in selective stabilization of individual new spines during circuit plasticity. Using two-photon glutamate uncaging, we stimulated nascent spines on dendrites of rat hippocampal CA1 neurons with patterns that induce LTP and then monitored spine survival rates using time-lapse imaging. Remarkably, we found that LTP-inducing stimuli increased the long-term survivorship (Ͼ14 h) of individual new spines. Activity-induced new spine stabilization required NMDA receptor activation and was specific for stimuli that induced LTP. Moreover, abrogating CaMKII binding to the NMDA receptor abolished activity-induced new spine stabilization. Our findings demonstrate for the first time that, in addition to enhancing the efficacy of preexisting synapses, LTP-inducing stimuli promote the transition of nascent spines from a short-lived, transient state to a longer-lived, persistent state.

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Interactions between the NR2B Receptor and CaMKII Modulate Synaptic Plasticity and Spatial Learning

Cited by 159 publications

References 56 publications

Interaction Between CaMKII and GluN2B Controls ERK-Dependent Plasticity

Interaction Between CaMKII and GluN2B Controls ERK-Dependent Plasticity

Decreased NR2B Subunit Synaptic Levels Cause Impaired Long-Term Potentiation But Not Long-Term Depression

LTP-Induced Long-Term Stabilization of Individual Nascent Dendritic Spines

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