- Open Access
The CaMKII/NMDAR complex as a molecular memory
© Sanhueza and Lisman; licensee BioMed Central Ltd. 2013
- Received: 6 December 2012
- Accepted: 17 January 2013
- Published: 14 February 2013
CaMKII is a major synaptic protein that is activated during the induction of long-term potentiation (LTP) by the Ca2+ influx through NMDARs. This activation is required for LTP induction, but the role of the kinase in the maintenance of LTP is less clear. Elucidating the mechanisms of maintenance may provide insights into the molecular processes that underlie the stability of stored memories. In this brief review, we will outline the criteria for evaluating an LTP maintenance mechanism. The specific hypothesis evaluated is that LTP is maintained by the complex of activated CaMKII with the NMDAR. The evidence in support of this hypothesis is substantial, but further experiments are required, notably to determine the time course and persistence of complex after LTP induction. Additional work is also required to elucidate how the CaMKII/NMDAR complex produces the structural growth of the synapse that underlies late LTP. It has been proposed by Frey and Morris that late LTP involves the setting of a molecular tag during LTP induction, which subsequently allows the activated synapse to capture the proteins responsible for late LTP. However, the molecular processes by which this leads to the structural growth that underlies late LTP are completely unclear. Based on known binding reactions, we suggest the first molecularly specific version of tag/capture hypothesis: that the CaMKII/NMDAR complex, once formed, serves as a tag, which then leads to a binding cascade involving densin, delta-catenin, and N-cadherin (some of which are newly synthesized). Delta-catenin binds AMPA-binding protein (ABP), leading to the LTP-induced increase in AMPA channel content. The addition of postsynaptic N-cadherin, and the complementary increase on the presynaptic side, leads to a trans-synaptically coordinated increase in synapse size (and more release sites). It is suggested that synaptic strength is stored stably through the combined actions of the CaMKII/NMDAR complex and N-cadherin dimers. These N-cadherin pairs have redundant storage that could provide informational stability in a manner analogous to the base-pairing in DNA.
- Basal Transmission
- Mutation L1298A
- AMPA Channel
- Synapse Size
- CaMKII Holoenzyme
LTP induction should cause a persistent increase in the CaMKII/NMDAR complex.
Inhibiting formation of the CaMKII/NMDAR complex should block LTP induction.
Decreasing the amount of CaMKII/NMDAR complex after LTP induction should reverse LTP.
A component of basal transmission should be reversed by reducing the basal CaMKII/NMDAR complex.
There must be a mechanism by which CaMKII/NMDAR complex can produce potentiation, specifically the trans-synaptic structural processes that underlie late LTP.
The initial evidence that CaMKII could interact with the NMDAR came from in vitro experiments showing that a fragment of GluN2B is a substrate for purified CaMKII (at 1303) . It was noted that the binding affinity of GluN2B was much higher than for other CaMKII substrates. Subsequent experiments showed that CaMKII could form a tight complex with NMDAR and that the complex was present in living cells, as identified by crosslinking or coimmunoprecipitation (co-IP) [8–10]. Importantly, the amount of complex was increased substantially by stimulation that elevated intracellular Ca2+ and thereby activated CaMKII.
A critical assumption of the proposed model is that LTP produces an increase in the CaMKII/NMDAR complex that is persistent for the duration of LTP. This assumption remains to be tested directly, but there is relevant evidence. Stimulation of cultured neurons with glutamate/glycine (a form of chemical LTP) can trigger persistent translocation of CaMKII that requires kinase binding to GluN2B at what is termed the T-site . Importantly, the persistently translocated CaMKII is phosphorylated at T286 . Furthermore, chemical LTP produces translocation of CaMKII to the PSD, as visualized by electron microscopy; this persists for at least 1 hr after LTP induction, suggesting that there is persistent formation of the CaMKII/NMDAR complex [13, 14].
The binding of CaMKII to the NMDAR requires an activated open form of the kinase. Therefore, the recent optical experiments  demonstrating that CaMKII is only transiently activated after LTP induction (~1 minute) could suggest that the CaMKII/NMDAR complex is also transient. However, there are two reasons to doubt the generality of this conclusion. First, recent measurements indicate that the fraction of CaMKII subunits directly bound to the NMDAR and thereby locked in the open confirmation  is a small fraction of the total CaMKII in spines and may be difficult to detect optically . Second, the optical measurements of CaMKII activation were made under conditions that did not evoke late LTP , raising the possibility that future measurement under conditions that did induce late LTP would evoke a detectable persistent component, as seen with induction protocols based on tetanic stimulation . In any case, given that the key question is the duration of the LTP-induced increase in CaMKII/NMDAR complex, what is needed is a method (possibly based on FRET) that would make it possible to directly monitor the kinetics of complex formation and persistence.
To examine the functional role of complex formation, Barria and Malinow  overexpressed a form of GluN2B having mutations near the CaMKII phosphorylation site (R1300Q and S1303D) that strongly interferes with binding . LTP was examined using a low-frequency pairing protocol. There was a significant (but not complete) block of potentiation in the first 10 minutes after LTP induction; at later times, the block was complete.
Related experiments were conducted in hippocampal slices from knockin (KI) mice in which CaMKII-GluN2B binding was impaired by the mutations L1298A and R1300Q . In these mice, the basal CaMKII/NMDAR complex was reduced by about 40%. Activity-dependent formation of complex in cell cultures was more strongly reduced. LTP induced by high-frequency stimulation in slice experiments was reduced, but only by about 50%. It is unclear whether the smaller reduction than in the Barria/Malinow experiments is due to a slightly different mutation, to the difference in animal age, or to a difference in the LTP induction protocol.
Another method for interfering with the CaMKII/NMDAR complex utilized transgenic mice in which the whole C-terminal GluN2B fragment could be induced . The LTP induced by high-frequency stimulation was reduced by about 50%. It is unclear whether this reduction was due to inhibiting CaMKII activity or to inhibiting the formation of the CaMKII/NMDAR complex.
A complementary experiment would be to determine the effects of increasing the CaMKII/NMDAR complex. Overexpression of activated CaMKII holoenzyme increases synaptic strength and spine size, provided that phosphorylation of T305/306 is prevented . It would be expected that this form of holoenzyme would increase the CaMKII/NMDAR complex and synapse size, but this has not been directly tested.
An important tool has been the development of a related group of peptides (CN27; CN21; CN19) that block the formation of the CaMKII/NMDAR complex in vitro. This peptide family derives from a fragment of an endogenous CaMKII inhibitor protein, CaMKIIN . This protein strongly binds to a site on CaMKII (the T-site) in addition to the catalytic site to which other peptide inhibitors mainly bind (these are based on the sequence of the CaMKII regulatory domain). It is to the T-site that the NMDAR itself binds.
Several controls point to the fact that CN21 works in slices to reduce the CaMKII/NMDAR complex, as expected from in vitro work. First, the peptide reduced the amount of basal complex, as measured by co-IP (basal transmission was also reduced; see next section). If somewhat lower concentrations of CN21 were used (5 μM instead of 20 μM), there was no reduction in the CaMKII/NMDAR complex and no persistent reduction in basal transmission. Second, the peptide produced a small but statistically significant reduction in the amount of CaMKII bound in spines. Third, CN21 produced a large reduction in the activity-dependent increase of CaMKII in the PSD .
The ability of CN compounds to rapidly reverse LTP is not shared by other peptides that primarily inhibit the CaMKII catalytic site [29, 30]. This suggests that the reversal is due to interference with structural rather than enzymatic reactions. This could mean that there is no role for enzymatic activity (including autophosphorylation-induced autonomous activity ) during LTP maintenance. Alternatively, the effects of inhibiting such activity may require many hours to develop and thus have not been seen in the much shorter experiments performed thus far. Indeed, experiments have shown that although phosphatase is present in the PSD, there is negligible dephosphorylation of CaMKII T286 within 1 hr .
LTP has been observed in vivo during learning [32, 33]. Moreover, synapses that have undergone learning-dependent LTP cannot then undergo LTP by electrical stimulation. This occlusion suggests that learning has saturated the normal LTP process. It would thus be expected that at least part of basal transmission, as measured in hippocampal slices, is the result of LTP-like events that occurred while the animal was alive. This inference is confirmed by analysis of unitary responses in the slice: the stronger the basal transmission, the smaller the magnitude of the LTP that can be induced [34, 35].
Based on the data outline in the above paragraph, a strong expectation is that an agent that affects a synaptic memory mechanism should reduce basal transmission. Consistent with this, CN compounds depress basal transmission . Moreover, this depression persists after removal of the CN compound, and the LTP that can then be induced is larger than if a scrambled control peptide or no peptide had been applied.
CN-induced depression is observed for drug concentrations necessary to disrupt basal CaMKII-NMDAR interaction in the slices, but not for lower concentrations causing only kinase inhibition . Moreover, this type of depression is different from known forms of activity-dependent long-term depression (LTD), and it does not require Ca2+ influx, protein synthesis, or degradation . The CN-induced persistent depression was barely detected in very young animals (P7-P10; ) for which CaMKII content at synapses is comparatively much lower [37, 38]. Taken together, these findings strongly suggest that CN-induced depression of basal transmission is caused by breakdown of the CaMKII-NMDAR interaction at the synapse. Perhaps inconsistent with this conclusion is the fact that basal transmission was not reduced when the basal level of CaMKII/NMDAR complex was reduced by knockin of NMDAR mutations . However, it is difficult to interpret such knockin experiments because known homeostatic processes could have normalized transmission over the lifetime of the animal.
There must be a mechanism by which CaMKII/NMDAR complex can lead to the trans-synaptic structural growth that underlies late LTP
LTP has an early phase that does not involve synapse growth and does not require protein synthesis; this is followed within ~1 hr by late LTP, which involves synapse growth and requires protein synthesis [39, 40]. An important concept is the tag and capture model . According to this model, strong stimulation leads to “tagging” of the stimulated synapse by addition of a protein; this then serves to capture newly synthesized proteins, leading to late LTP at the activated synapse. Evidence suggests that CaMKII is the tag [42, 43].
Relatively little is known about how proteins produce the synaptic growth that underlies late LTP. One area of progress has established a key role for N-cadherin, a homophilic adhesion molecule that forms a trans-synaptic linkage between the presynaptic and postsynaptic sides of the synapse. Pharmacological experiments, gene knockout experiments, conditional knockout experiments, and RNAi experiments all show that N-cadherin is required for late LTP (but not for early LTP) [44–46]. Furthermore, LTP induction causes synthesis of N-cadherin and its insertion into the synapse . Finally, electron microscopy shows that overexpression of N-cadherin can increase synapse size . Thus, although there are many forms of adhesion molecules at synapses, N-cadherin appears to be of central importance in late LTP.
Physiological analysis suggests that late LTP involves both addition of AMPA receptors and an increase in presynaptic release sites [53, 54]. It is thus of interest that delta-catenin binds to AMPA-binding protein (ABP)  and may thereby increase the AMPA channel (notably GluA2) content of the synapse [56–58]. N-cadherin can also bind directly to GluA2 , see also . There is relatively little that can be said about the presynaptic changes that lead to enhanced vesicle release. It is known that overexpression of postsynaptic N-cadherin affects presynaptic function , but how this happens is unclear. Perhaps presynaptic N-cadherin is brought into the synapse simply by binding to postsynaptic N-cadherin. Alternatively, insertion of presynaptic N-cadherin might depend on the presynaptic activation of CaMKII , translocation of CaMKII to the presynaptic grid , and a protein linkage to N-cadherin  analogous to the postsynaptic linkage described in Figure 2.
It is noteworthy that Figure 3 suggests a limited analogy to DNA: just as in DNA, there are two crosslinked backbone structures attached to elements that link the two backbone structures by a pairing rule (in DNA, the rule is heterologous; here, it is homologous). The existence of two backbone structures provides redundant information storage. Thus the N-cadherin dimers could contribute to informational stability, just as base-pairing does in DNA. Specifically, if one member of an N-cadherin dimer was lost in the process of turnover, the existence of the other member could serve as a basis for repair. In this way, the number of N-cadherin dimers could be stable despite turnover of N-cadherin. This stability, in turn, could help to stabilize the CaMKII/NMDAR complex, as described in the next paragraph.
Although we have posited that the CaMKII/NMDAR complex brings about the capture of the protein complex that includes actinin, densin, delta-catenin, and N-cadherin, the complex, once established, may be important for the stabilization of CaMKII/NMDAR complex during protein turnover. During turnover of CaMKII, phosphorylated CaMKII holoenzymes may be removed from the NMDAR, leaving a pocket formed by densin and actinin. This pocket is relatively stable because it is held there by other parts of the complex that include the N-cadherin dimmers (Figure 2). The phospho-CaMKII that left the pocket can be replaced by CaMKII that is either not phosphorylated (but with Ca2+/calmodulin bound) or weakly phosphorylated. There, CaMKII can bind to GluN2B  and will become autophosphorylated as a result of stimulation by actinin  and GluN2B  and because PSD CaMKII is protected from phosphatase  (probably because of the protein structure around bound CaMKII). This highly phosphorylated state then leads to tighter binding to the NMDAR . In this way, the original tight complex of CaMKII bound to the NMDAR can be restored despite the molecular turnover.
This model provides an explanation for why overexpression of catalytically dead CaMKII can reverse memory (see next section). Specifically, this form (K42M) can bind to the NMDAR (albeit weakly), but not undergo the autophosphorylation necessary for tight binding to the NMDAR  and densin . Weak binding to the NMDAR and densin may ultimately lead to dissociation of the entire complex, resulting in loss of LTP and memory.
Our model leads to testable predictions: that densin-180, delta-catenin, and N-cadherin are required for synapse growth and late LTP. As noted earlier, N-cadherin is required for late LTP (but not early LTP) and for synapse growth. Knockout of delta-catenin or densin does not block early LTP [58, 66]; the effect on late LTP or synapse growth has not been tested.
Evidence that CaMKII signaling contributes strongly to the maintenance of nonspatial forms of memory has recently been published. One line of work comes from research on addiction in rats . It was found that a persistent reversal of drug-induced sensitization could be produced by transient expression of a kinase-dead CaMKII mutant (K42M). In these experiments, animals were initially subjected to repetitive amphetamine exposure. Subsequently, transient virally mediated expression of K42M produced a persistent block of the normal long-lasting behavioral response to the drug (enhanced locomotion and drug self-administration). Because expression of K42M had ceased at the time of testing, the action of K42M must have been to reset a memory switch. In addition to the lack of catalytic activity and autophosphorylation, K42M displays an altered pattern of synaptic translocation in cultured neurons. While transient translocation is not affected [68, 69], the strength of binding to the NMDAR is strongly decreased [21, 70]. Thus, there is a reasonable basis for suspecting that K42M can erase a memory by acting as a dominant negative for stable CaMKII/NMDAR complex. A further indication that CaMKII is involved in the maintenance of behavioral memory comes from the experiments of . They found that conditioned fear could be erased by transient post-learning inhibition of overexpressed CaMKII. However, the inhibition was animal-wide, so the location and physiological correlate of this effect are unclear.
Recent experiments have sought to test directly the role of the CaMKII/NMDAR complex in memory. To address this issue,  utilized a knockin mouse with mutations L1298A and R1300Q in GluN2B that interfere with that interferes with the formation of the CaMKII/NMDAR complex. A key finding was that spatial memory in the Morris water maze task, when measured at 1 or 3 days after the last training session, was greatly reduced (memory 1-2 hr after each training session was not reduced). Interpretation of the results is complicated by the fact that the mutation only produced a partial reduction in the basal CaMKII/NMDAR complex and only a ~50% reduction in LTP. It is thus possible that the learning that occurred in this task was due to this remaining ability of complex to form. It is also of interest to consider the possibility that CaMKII can form other complexes (i.e., not with NMDARs) that contribute to synaptic enhancement. Indeed, if presynaptic CaMKII is necessary for binding of N-cadherin and growth of the presynaptic active zone, the binding of CaMKII to a presynaptic protein, possibly Ca2+ channels , could contribute to presynaptic structural changes during LTP. A further question is whether memory maintenance can be reversed by interfering with the CaMKII/NMDAR complex after learning. Only one study thus far deals with this issue . It was found that a CN peptide injected into the cingulate cortex was able to reverse a form of central pain. Importantly, induction of central pain produced a large increase in the amount of CaMKII/NMDAR complex in PSDs of the cingulate, and this increase was reversed by CN.
It is noteworthy that a major alternative hypothesis , that memory is stored by a persistent increase in PKM-zeta, has substantial weaknesses, many of which have only recently become apparent. A critical test of the effect of PKM-zeta to reverse LTP maintenance has not been done. While it was shown that LTP in the slice could be reduced by ZIP, it was not shown that this reduction persisted after removal of ZIP . In different experiments in which ZIP was transiently injected in vivo, the drug was still present 2 hr after injection, as shown by immunochemistry; no removal of drug was demonstrated . Thus, the existing experiments do not distinguish between effects on LTP maintenance and effects on LTP expression. Furthermore, recent work casts strong doubt on whether ZIP has its effect by an action on PKM-zeta [1, 77, 78]. Importantly, recent work from the Sacktor laboratory demonstrates that the control peptide (scrambled ZIP) can also inhibit PKM-zeta and is only three times less effective than ZIP . With such small differences in efficacy, it would take very precise administration of these peptides to produce a differential effect, but the concentrations used in in vivo experiments were highly imprecise (several orders of magnitude above the Kd) . Thus, the differential effects on ZIP and scrambled ZIP are probably due to an effect on some target other than PKM-zeta. Finally, knockout of this enzyme did not affect late LTP, memory, or the effect of ZIP  (but see ). Thus, the evidence that PKM-zeta is the molecular basis of memory is not compelling.
The CaMKII/NMDAR complex is a promising candidate as the molecular basis of memory storage. Although there is increasing evidence that CaMKII and its binding partners form a molecular memory, additional work is required to prove this hypothesis. In particular, methods for studying the formation and persistence of the complex during actual LTP are needed. Furthermore, much additional work is required at the behavioral level to test the role of the CaMKII and the CaMKII/NMDAR complex in the persistence of memory. Most of the work on this complex has been done in the hippocampus Thus, it will be of particular importance to determine whether interference with the complex in the hippocampus can reverse a hippocampal-dependent spatial memory.
An important unresolved question is whether the importance of CaMKII/NMDAR complex in LTP maintenance, as demonstrated in Figure 1, will be specific for CA1 or more generally applicable to synapses. One perspective on this question comes from analysis of the PSDs, which are generally isolated from whole brains. Structural analysis shows that these PSDs are nearly tight-packed with CaMKII . Given that these PSDs are representative of the whole brain, it seems likely that a critical role for CaMKII will be a widespread property. It has become increasingly clear that an important aspect of activity-dependent synaptic plasticity is the making and breaking of synaptic connections. Recent work shows that the ability of activity to stabilize synaptic connections is dependent on the CaMKII/NMDAR complex . Thus, similar mechanisms may be involved in changes in synaptic strength and in stabilization of synaptic connections.
We thank Nikolai Otmakhov and Roger Colbran for comments on the manuscript. This work was supported by grants from the Ellison Foundation (J.L.), NIH Award Number R01DA027807 from the National Institute on Drug Abuse (J.L.), and University of Chile VID ENL-3/12 (M.S.).
- Lisman J, Yasuda R, Raghavachari S: Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci. 2012, 13 (3): 169-182.PubMed CentralGoogle Scholar
- Faas G, et al: Calmodulin as a direct detector of Ca2+ signals. Nat Neurosci. 2011, 14 (3): 301-304. 10.1038/nn.2746.PubMed CentralGoogle Scholar
- Benke TA, et al: Modulation of AMPA receptor unitary conductance by synaptic activity. Nature. 1998, 393 (6687): 793-797. 10.1038/31709.Google Scholar
- Kristensen AS, et al: Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating. Nat Neurosci. 2011, 14 (6): 727-35. 10.1038/nn.2804.PubMed CentralGoogle Scholar
- Tomita S, et al: Bidirectional synaptic plasticity regulated by phosphorylation of stargazin-like TARPs. Neuron. 2005, 45 (2): 269-77. 10.1016/j.neuron.2005.01.009.Google Scholar
- Opazo P, et al: CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron. 2010, 67 (2): 239-252. 10.1016/j.neuron.2010.06.007.Google Scholar
- Omkumar RV, et al: Identification of a phosphorylation site for calcium/calmodulindependent protein kinase II in the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem. 1996, 271 (49): 31670-31678. 10.1074/jbc.271.49.31670.Google Scholar
- Strack S, Colbran RJ: Autophosphorylation-dependent targeting of calcium/ calmodulin-dependent protein kinase II by the NR2B subunit of the N-methyl- D-aspartate receptor. J Biol Chem. 1998, 273 (33): 20689-20692. 10.1074/jbc.273.33.20689.Google Scholar
- Gardoni F, et al: Calcium/calmodulin-dependent protein kinase II is associated with NR2A/B subunits of NMDA receptor in postsynaptic densities. J Neurochem. 1998, 71 (4): 1733-1741.Google Scholar
- Leonard AS, et al: Calcium/calmodulin-dependent protein kinase II is associated with the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA. 1999, 96 (6): 3239-3244. 10.1073/pnas.96.6.3239.PubMed CentralGoogle Scholar
- Bayer KU, et al: Transition from reversible to persistent binding of CaMKII to postsynaptic sites and NR2B. J Neurosci. 2006, 26 (4): 1164-1174. 10.1523/JNEUROSCI.3116-05.2006.PubMed CentralGoogle Scholar
- Appleby VJ, et al: LTP in hippocampal neurons is associated with a CaMKII-mediated increase in GluA1 surface expression. J Neurochem. 2011, 116 (4): 530-543. 10.1111/j.1471-4159.2010.07133.x.Google Scholar
- Otmakhov N, et al: Persistent accumulation of calcium/calmodulin-dependent protein kinase II in dendritic spines after induction of NMDA receptor-dependent chemical long-term potentiation. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2004, 24 (42): 9324-31. 10.1523/JNEUROSCI.2350-04.2004.Google Scholar
- Zhang YP, Holbro N, Oertner TG: Optical induction of plasticity at single synapses reveals input-specific accumulation of alphaCaMKII. Proc Natl Acad Sci USA. 2008, 105 (33): 12039-44. 10.1073/pnas.0802940105.PubMed CentralGoogle Scholar
- Lee SJ, Yasuda R: Spatiotemporal Regulation of Signaling in and out of Dendritic Spines: CaMKII and Ras. The open neuroscience journal. 2009, 3: 117-127. 10.2174/1874082000903020117.PubMed CentralGoogle Scholar
- Bayer KU, et al: Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature. 2001, 411 (6839): 801-5. 10.1038/35081080.Google Scholar
- Feng B, Raghavachari S, Lisman J: Quantitative estimates of the cytoplasmic, PSD, and NMDAR-bound pools of CaMKII in dendritic spines. Brain Res. 2011, 1419: 46-52.PubMed CentralGoogle Scholar
- Tanaka J-I, et al: Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science. 2008, 319 (5870): 1683-1687. 10.1126/science.1152864.PubMed CentralGoogle Scholar
- Fukunaga K, et al: Long-term potentiation is associated with an increased activity of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 1993, 268 (11): 7863-7.Google Scholar
- Barria A, Malinow R: NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron. 2005, 48 (2): 289-301. 10.1016/j.neuron.2005.08.034.Google Scholar
- Strack S, McNeill RB, Colbran RJ: Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem. 2000, 275 (31): 23798-806. 10.1074/jbc.M001471200.Google Scholar
- Halt A, et al: CaMKII binding to GluN2B is critical during memory consolidation. EMBO J. 2012, 31 (5): 1203-1216. 10.1038/emboj.2011.482.PubMed CentralGoogle Scholar
- Zhou Y, et al: Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning. J Neurosci. 2007, 27 (50): 13843-13853. 10.1523/JNEUROSCI.4486-07.2007.Google Scholar
- Pi HJ, et al: CaMKII control of spine size and synaptic strength: role of phosphorylation states and nonenzymatic action. Proc Natl Acad Sci USA. 2010, 107 (32): 14437-42. 10.1073/pnas.1009268107.PubMed CentralGoogle Scholar
- Vest RS, et al: Dual mechanism of a natural CaMKII inhibitor. Mol Biol Cell. 2007, 18 (12): 5024-33. 10.1091/mbc.E07-02-0185.PubMed CentralGoogle Scholar
- Chang BH, Mukherji S, Soderling TR: Characterization of a calmodulin kinase II inhibitor protein in brain. Proc Natl Acad Sci USA. 1998, 95 (18): 10890-5. 10.1073/pnas.95.18.10890.PubMed CentralGoogle Scholar
- Sanhueza M, et al: Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength. J Neurosci. 2011, 31 (25): 9170-9178. 10.1523/JNEUROSCI.1250-11.2011.PubMed CentralGoogle Scholar
- Dosemeci A, et al: The effect of CaMKII inhibitor tatCN21 on the re-distribution of CaMKII and SynGAP in hippocampal neurons under excitatory conditions. SFN Program#/Poster#: 43.15/C53. In Society for Neuroscience. 2012, New OrleansGoogle Scholar
- Otmakhov N, Griffith LC, Lisman JE: Postsynaptic inhibitors of calcium/calmodulin-dependent protein kinase type II block induction but not maintenance of pairing-induced long-term potentiation. J Neurosci. 1997, 17 (14): 5357-5365.Google Scholar
- Chen HX, et al: Is persistent activity of calcium/calmodulin-dependent kinase required for the maintenance of LTP?. J Neurophysiol. 2001, 85 (4): 1368-1376.Google Scholar
- Mullasseril P, et al: A structural mechanism for maintaining the ‘on-state’ of the CaMKII memory switch in the post-synaptic density. J Neurochem. 2007, 103 (1): 357-64.PubMed CentralGoogle Scholar
- Gruart A, Munoz MD, Delgado-Garcia JM: Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2006, 26 (4): 1077-87. 10.1523/JNEUROSCI.2834-05.2006.Google Scholar
- Whitlock JR, et al: Learning induces long-term potentiation in the hippocampus. Science. 2006, 313 (5790): 1093-7. 10.1126/science.1128134.Google Scholar
- Liao D, Jones A, Malinow R: Direct measurement of quantal changes underlying long-term potentiation in CA1 hippocampus. Neuron. 1992, 9 (6): 1089-1097. 10.1016/0896-6273(92)90068-O.Google Scholar
- Debanne D, Gahwiler BH, Thompson SM: Heterogeneity of synaptic plasticity at unitary CA3-CA1 and CA3-CA3 connections in rat hippocampal slice cultures. The Journal of neuroscience: the official journal of the Society for Neuroscience. 1999, 19 (24): 10664-71.Google Scholar
- Gouet C, et al: On the Mechanism of Synaptic Depression Induced by CaMKIIN, an Endogenous Inhibitor of CaMKII. PLoS One. 2012, 7 (11): e49293-10.1371/journal.pone.0049293.PubMed CentralGoogle Scholar
- Petralia RS, et al: Ontogeny of postsynaptic density proteins at glutamatergic synapses. Mol Cell Neurosci. 2005, 29 (3): 436-52. 10.1016/j.mcn.2005.03.013.PubMed CentralGoogle Scholar
- Swulius MT, et al: Structure and composition of the postsynaptic density during development. J Comp Neurol. 2010, 518 (20): 4243-60. 10.1002/cne.22451.PubMed CentralGoogle Scholar
- Bailey CH, Kandel ER: Synaptic remodeling, synaptic growth and the storage of long-term memory in Aplysia. Prog Brain Res. 2008, 169: 179-198.Google Scholar
- Bourne JN, Harris KM: Coordination of size and number of excitatory and inhibitory synapses results in a balanced structural plasticity along mature hippocampal CA1 dendrites during LTP. Hippocampus. 2011, 21 (4): 354-73. 10.1002/hipo.20768.PubMed CentralGoogle Scholar
- Frey U, Morris RG: Synaptic tagging and long-term potentiation. Nature. 1997, 385 (6616): 533-536. 10.1038/385533a0.Google Scholar
- Garic A, et al: CaMKII activation is a novel effector of alcohol’s neurotoxicity in neural crest stem/progenitor cells. J Neurochem. 2011, 118 (4): 646-57. 10.1111/j.1471-4159.2011.07273.x.PubMed CentralGoogle Scholar
- Redondo RL, et al: Synaptic tagging and capture: differential role of distinct calcium/calmodulin kinases in protein synthesis-dependent long-term potentiation. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2010, 30 (14): 4981-9. 10.1523/JNEUROSCI.3140-09.2010.Google Scholar
- Bozdagi O, et al: Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. Neuron. 2000, 28 (1): 245-59. 10.1016/S0896-6273(00)00100-8.Google Scholar
- Bozdagi O, et al: Persistence of coordinated long-term potentiation and dendritic spine enlargement at mature hippocampal CA1 synapses requires N-cadherin. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2010, 30 (30): 9984-9. 10.1523/JNEUROSCI.1223-10.2010.Google Scholar
- Tang L, Hung CP, Schuman EM: A role for the cadherin family of cell adhesion molecules in hippocampal long-term potentiation. Neuron. 1998, 20 (6): 1165-75. 10.1016/S0896-6273(00)80497-3.Google Scholar
- Mendez P, et al: N-cadherin mediates plasticity-induced long-term spine stabilization. J Cell Biol. 2010, 189 (3): 589-600. 10.1083/jcb.201003007.PubMed CentralGoogle Scholar
- Walikonis RS, et al: Densin-180 forms a ternary complex with the (alpha)-subunit of Ca2+/calmodulin-dependent protein kinase II and (alpha)-actinin. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2001, 21 (2): 423-33.Google Scholar
- Robison AJ, et al: Multivalent Interactions of Calcium/Calmodulin-dependent Protein Kinase II with the Postsynaptic Density Proteins NR2B, Densin-180, and α-Actinin-2. J Biol Chem. 2005, 280 (42): 35329-35336. 10.1074/jbc.M502191200.Google Scholar
- Izawa I, et al: Densin-180 interacts with delta-catenin/neural plakophilin-related armadillo repeat protein at synapses. J Biol Chem. 2002, 277 (7): 5345-50. 10.1074/jbc.M110052200.Google Scholar
- Brigidi GS, Bamji SX: Cadherin-catenin adhesion complexes at the synapse. Curr Opin Neurobiol. 2011, 21 (2): 208-14. 10.1016/j.conb.2010.12.004.Google Scholar
- Lisman JE, Harris KM: Quantal analysis and synaptic anatomy–integrating two views of hippocampal plasticity. Trends Neurosci. 1993, 16 (4): 141-7. 10.1016/0166-2236(93)90122-3.Google Scholar
- Lisman J: The pre/post LTP debate. Neuron. 2009, 63 (3): 281-284. 10.1016/j.neuron.2009.07.020.Google Scholar
- Lisman J, Raghavachari S: A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Science’s signal transduction knowledge environment. 2006, 2006 (356): re11-re11.Google Scholar
- Silverman JB, et al: Synaptic anchorage of AMPA receptors by cadherins through neural plakophilin-related arm protein-AMPA receptor-binding protein complexes. J Neurosci. 2007, 27 (32): 8505-8516. 10.1523/JNEUROSCI.1395-07.2007.Google Scholar
- DeSouza S, et al: Differential Palmitoylation Directs the AMPA Receptor-Binding Protein ABP to Spines or to Intracellular Clusters. J Neurosci. 2002, 22 (9): 3493-3503.Google Scholar
- Ochiishi T, et al: Regulation of AMPA receptor trafficking by δ-catenin. Mol Cell Neurosci. 2008, 39 (4): 499-507. 10.1016/j.mcn.2008.06.002.Google Scholar
- Israely I, et al: Deletion of the neuron-specific protein delta-catenin leads to severe cognitive and synaptic dysfunction. Current biology: CB. 2004, 14 (18): 1657-63. 10.1016/j.cub.2004.08.065.Google Scholar
- Saglietti L, et al: Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron. 2007, 54 (3): 461-77. 10.1016/j.neuron.2007.04.012.Google Scholar
- Zhou Z, et al: GluA2 (GluR2) regulates metabotropic glutamate receptor-dependent long-term depression through N-cadherin-dependent and cofilin-mediated actin reorganization. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2011, 31 (3): 819-33. 10.1523/JNEUROSCI.3869-10.2011.Google Scholar
- Vitureira N, et al: Differential control of presynaptic efficacy by postsynaptic N-cadherin and [beta]-catenin. Nat Neurosci. 2012, 15 (1): 81-89.Google Scholar
- Lu FM, Hawkins RD: Presynaptic and postsynaptic Ca(2+) and CamKII contribute to long-term potentiation at synapses between individual CA3 neurons. Proc Natl Acad Sci USA. 2006, 103 (11): 4264-9. 10.1073/pnas.0508162103.PubMed CentralGoogle Scholar
- Shakiryanova D, et al: Differential control of presynaptic CaMKII activation and translocation to active zones. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2011, 31 (25): 9093-100. 10.1523/JNEUROSCI.0550-11.2011.Google Scholar
- Jalan-Sakrikar N, et al: Substrate-selective and calcium-independent activation of CaMKII by alpha-actinin. J Biol Chem. 2012, 287 (19): 15275-83. 10.1074/jbc.M112.351817.PubMed CentralGoogle Scholar
- Strack S, et al: Association of calcium/calmodulin-dependent kinase II with developmentally regulated splice variants of the postsynaptic density protein densin-180. J Biol Chem. 2000, 275 (33): 25061-4. 10.1074/jbc.C000319200.Google Scholar
- Carlisle HJ, et al: Deletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2011, 31 (45): 16194-207. 10.1523/JNEUROSCI.5877-10.2011.Google Scholar
- Loweth JA, et al: Persistent Reversal of Enhanced Amphetamine Intake by Transient CaMKII Inhibition. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2013, 33 (4): 1411-6. 10.1523/JNEUROSCI.4386-13.2013.Google Scholar
- Shen K, Meyer T: Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. Science. 1999, 284 (5411): 162-6. 10.1126/science.284.5411.162.Google Scholar
- Yamagata Y, et al: Kinase-dead knock-in mouse reveals an essential role of kinase activity of Ca2+/calmodulin-dependent protein kinase IIalpha in dendritic spine enlargement, long-term potentiation, and learning. J Neurosci. 2009, 29 (23): 7607-7618. 10.1523/JNEUROSCI.0707-09.2009.Google Scholar
- O’Leary H, et al: Nucleotides and phosphorylation bi-directionally modulate Ca2+/calmodulin-dependent protein kinase II (CaMKII) binding to the N-methyl-D-aspartate (NMDA) receptor subunit GluN2B. J Biol Chem. 2011, 286 (36): 31272-81. 10.1074/jbc.M111.233668.PubMed CentralGoogle Scholar
- Wang H, et al: Inducible protein knockout reveals temporal requirement of CaMKII reactivation for memory consolidation in the brain. Proc Natl Acad Sci USA. 2003, 100 (7): 4287-92. 10.1073/pnas.0636870100.PubMed CentralGoogle Scholar
- Jiang X, et al: Modulation of CaV2.1 channels by Ca2+/calmodulin-dependent protein kinase II bound to the C-terminal domain. Proc Natl Acad Sci USA. 2008, 105 (1): 341-346. 10.1073/pnas.0710213105.PubMed CentralGoogle Scholar
- Li Y, et al: Phosphorylated CaMKII post-synaptic binding to NR2B subunits in the anterior cingulate cortex mediates visceral pain in visceral hypersensitive rats. J Neurochem. 2012, 121 (4): 662-671. 10.1111/j.1471-4159.2012.07717.x.Google Scholar
- Sacktor T: Memory maintenance by PKMzeta – an evolutionary perspective. Mol Brain. 2012, 5 (1): 31-31. 10.1186/1756-6606-5-31.PubMed CentralGoogle Scholar
- Serrano P, Yao Y, Sacktor T: Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation. J Neurosci. 2005, 25 (8): 1979-1984. 10.1523/JNEUROSCI.5132-04.2005.Google Scholar
- Pastalkova E, et al: Storage of spatial information by the maintenance mechanism of LTP. Science. 2006, 313 (5790): 1141-4. 10.1126/science.1128657.Google Scholar
- Wu-Zhang A, et al: Cellular pharmacology of protein kinase Mζ (PKMζ) contrasts with its in vitro profile: implications for PKMζ as a mediator of memory. J Biol Chem. 2012, 287 (16): 12879-12885. 10.1074/jbc.M112.357244.PubMed CentralGoogle Scholar
- Lisman J: Memory erasure by very high concentrations of ZIP may not be due to PKM-zeta. Hippocampus. 2012, 22 (3): 648-649. 10.1002/hipo.20980.Google Scholar
- Yao Y, et al: Matching biochemical and functional efficacies confirm ZIP as a potent competitive inhibitor of PKMζ in neurons. Neuropharmacology. 2013, 64: 37-44.PubMed CentralGoogle Scholar
- Volk LJ, et al: PKM-zeta is not required for hippocampal synaptic plasticity, learning and memory. Nature. 2013, 493 (7432): 420-3. 10.1038/nature11802.Google Scholar
- Tsokas P, et al Conditional knockout of the PKC/PKMζ gene in the adult mouse hippocampus prevents L-LTP. in 2012 Society for Neuroscience Meeting: : New Orleans. 2012, SfN: LAGoogle Scholar
- Petersen JD, et al: Distribution of Postsynaptic Density (PSD)-95 and Ca2+/Calmodulin-Dependent Protein Kinase II at the PSD. J Neurosci. 2003, 23 (35): 11270-11278.Google Scholar
- Hamilton AM, et al: Activity-dependent growth of new dendritic spines is regulated by the proteasome. Neuron. 2012, 74 (6): 1023-30. 10.1016/j.neuron.2012.04.031.PubMed CentralGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.