Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mechanisms of CaMKII action in long-term potentiation

Nature Reviews Neuroscience volume 13, pages 169–182 (2012)Cite this article

Subjects

Key Points

  • The mechanisms that result in synapse-specific activation of calcium/calmodulin-dependent protein kinase II (CaMKII) have been determined.

  • CaMKII translocates to the synapse during long-term potentiation (LTP), in part owing to binding of CaMKII to the NMDA-type glutamate receptor (NMDAR).

  • One component of early LTP involves CaMKII phosphorylation of the AMPA-type glutamate receptor (AMPAR) subunit glutamate receptor 1 (GluR1), which increases the average channel conductance of AMPARs.

  • Early LTP also involves the phosphorylation of stargazin by CaMKII, which allows extrasynaptic AMPARs to bind to postsynaptic density protein 95 (PSD95), thereby anchoring more AMPARs at the synapse.

  • The molecular memory at a synapse may involve the formation of CaMKII–NMDAR complexes.

  • Late LTP involves spine and synapse growth, the underlying mechanisms of which are not known.

Abstract

Long-term potentiation (LTP) of synaptic strength occurs during learning and can last for long periods, making it a probable mechanism for memory storage. LTP induction results in calcium entry, which activates calcium/calmodulin-dependent protein kinase II (CaMKII). CaMKII subsequently translocates to the synapse, where it binds to NMDA-type glutamate receptors and produces potentiation by phosphorylating principal and auxiliary subunits of AMPA-type glutamate receptors. These processes are all localized to stimulated spines and account for the synapse-specificity of LTP. In the later stages of LTP, CaMKII has a structural role in enlarging and strengthening the synapse.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Synapse-specificity of the processes involved in long-term potentiation induction.
Figure 2: Role of CaMKII–NMDAR complex in long-term potentiation maintenance.
Figure 3: Role of CaMKII in AMPAR-mediated transmission during early long-term potentiation.
Figure 4: Mechanisms of expression processes by which CaMKII enhances AMPAR-mediated transmission.

References

  1. Abraham, W. C. How long will long-term potentiation last? Phil. Trans. R. Soc. B. 358, 735–744 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Whitlock, J. R., Heynen, A. J., Shuler, M. G. & Bear, M. F. Learning induces long-term potentiation in the hippocampus. Science 313, 1093–1097 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Gruart, A., Munoz, M. D. & Delgado-Garcia, J. M. Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice. J. Neurosci. 26, 1077–1087 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Grant, S. G. & Silva, A. J. Targeting learning. Trends Neurosci. 17, 71–75 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Kerchner, G. A. & Nicoll, R. A. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nature Rev. Neurosci. 9, 813–825 (2008).

    Article  CAS  Google Scholar 

  6. Lisman, J., Schulman, H. & Cline, H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nature Rev. Neurosci. 3, 175–190 (2002).

    Article  CAS  Google Scholar 

  7. Chao, L. H. et al. A mechanism for tunable autoinhibition in the structure of a human Ca2+/calmodulin- dependent kinase II holoenzyme. Cell 146, 732–745 (2011). A breakthrough paper that provides the first crystal structure of the CaMKII holoenzyme. It should be noted, however, that the crystallized isoform is not the alpha or beta isoform, which are the most prevalent forms in the brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lisman, J. E. A mechanism for memory storage insensitive to molecular turnover: a bistable autophosphorylating kinase. Proc. Natl Acad. Sci. USA 82, 3055–3057 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Miller, S. G. & Kennedy, M. B. Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch. Cell 44, 861–870 (1986). A study showing that purified CaMKII can become persistently active following autophosphorylation.

    Article  CAS  PubMed  Google Scholar 

  10. Lledo, P. M. et al. Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. Proc. Natl Acad. Sci. USA 92, 11175–11179 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pi, H. J. et al. CaMKII control of spine size and synaptic strength: role of phosphorylation states and nonenzymatic action. Proc. Natl Acad. Sci. USA 107, 14437–14442 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Giese, K. P., Fedorov, N. B., Filipkowski, R. K. & Silva, A. J. Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science 279, 870–873 (1998). This paper demonstrates that mutation of a single amino acid, T286, onCaMKIIα prevents LTP induction and has profound effects on memory.

    Article  CAS  PubMed  Google Scholar 

  13. Lucchesi, W., Mizuno, K. & Giese, K. P. Novel insights into CaMKII function and regulation during memory formation. Brain Res. Bull. 85, 2–8 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Lee, Y. S. & Silva, A. J. The molecular and cellular biology of enhanced cognition. Nature Rev. Neurosci. 10, 126–140 (2009).

    Article  CAS  Google Scholar 

  15. Hojjati, M. R. et al. Kinase activity is not required for αCaMKII-dependent presynaptic plasticity at CA3-CA1 synapses. Nature Neurosci. 10, 1125–1127 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Sanderson, J. L. & Dell'Acqua, M. L. AKAP signaling complexes in regulation of excitatory synaptic plasticity. Neuroscientist 17, 321–336 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Blitzer, R. D. et al. Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science 280, 1940–1942 (1998). Paper discussing the control of CaMKII activation by phosphatase and the role of cAMP in the control of phosphatase.

    Article  CAS  PubMed  Google Scholar 

  18. Andersen, P., Sundberg, S. H., Sveen, O. & Wigstrom, H. Specific long-lasting potentiation of synaptic transmission in hippocampal slices. Nature 266, 736–737 (1977).

    Article  CAS  PubMed  Google Scholar 

  19. Lynch, G. S., Dunwiddie, T. & Gribkoff, V. Heterosynaptic depression: a postsynaptic correlate of long-term potentiation. Nature 266, 737–739 (1977).

    Article  CAS  PubMed  Google Scholar 

  20. Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Takao, K. et al. Visualization of synaptic Ca2+ /calmodulin-dependent protein kinase II activity in living neurons. J. Neurosci. 25, 3107–3112 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee, S. J., Escobedo-Lozoya, Y., Szatmari, E. M. & Yasuda, R. Activation of CaMKII in single dendritic spines during long-term potentiation. Nature 458, 299–304 (2009). Study describing a breakthrough optical method that allows for the determination of the spatial and temporal properties of CaMKII activation during LTP induction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ascher, P. & Nowak, L. Early biophysics of the NMDA receptor channel. J. Physiol. 587, 4563–4564 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mainen, Z. F. et al. Two-photon imaging in living brain slices. Methods 18, 231–239, (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Emptage, N. J., Reid, C. A., Fine, A. & Bliss, T. V. Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses. Neuron 38, 797–804 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Kovalchuk, Y., Eilers, J., Lisman, J. & Konnerth, A. NMDA receptor-mediated subthreshold Ca2+ signals in spines of hippocampal neurons. J. Neurosci. 20, 1791–1799 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sabatini, B. L., Oertner, T. G. & Svoboda, K. The life cycle of Ca2+ ions in dendritic spines. Neuron 33, 439–452 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Sobczyk, A., Scheuss, V. & Svoboda, K. NMDA receptor subunit-dependent [Ca2+] signaling in individual hippocampal dendritic spines. J. Neurosci. 25, 6037–6046 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Santucci, D. M. & Raghavachari, S. The effects of NR2 subunit-dependent NMDA receptor kinetics on synaptic transmission and CaMKII activation. PLoS Comput. Biol. 4, e1000208 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Erreger, K., Dravid, S. M., Banke, T. G., Wyllie, D. J. & Traynelis, S. F. Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. J. Physiol. 563, 345–358 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schneggenburger, R. & Neher, E. Presynaptic calcium and control of vesicle fusion. Curr. Opin. Neurobiol. 15, 266–274 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Faas, G. C., Raghavachari, S., Lisman, J. E. & Mody, I. Calmodulin as a direct detector of Ca2+ signals. Nature Neurosci. 14, 301–304 (2011). This paper provides evidence showing that calmodulin binds calciumvery rapidly and so is likely to be the first molecule to bind calcium after it enters the cytoplasm. These properties make calmodulin an ideal calcium signal detector.

    Article  CAS  PubMed  Google Scholar 

  33. Neher, E. & Augustine, G. J. Calcium gradients and buffers in bovine chromaffin cells. J. Physiol. 450, 273–301 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Feng, B., Raghavachari, S. & Lisman, J. Quantitative estimates of the cytoplasmic, PSD, and NMDAR-bound pools of CaMKII in dendritic spines. Brain Res. 1419, 46–52 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee, S. J. & Yasuda, R. Spatiotemporal regulation of signaling in and out of dendritic spines: CaMKII and Ras. Open Neurosci. J. 3, 117–127 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yasuda, R. & Murakoshi, H. The mechanisms underlying the spatial spreading of signaling activity. Curr. Opin. Neurobiol. 21, 313–321 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shen, K. & Meyer, T. Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. Science 284, 162–166 (1999). A classic study that demonstrates that CaMKII translocates towards the synapse after activation.

    Article  CAS  PubMed  Google Scholar 

  38. Lin, B. et al. Theta stimulation polymerizes actin in dendritic spines of hippocampus. J. Neurosci. 25, 2062–2069 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ahmed, R., Zha, X. M., Green, S. H. & Dailey, M. E. Synaptic activity and F-actin coordinately regulate CaMKIIα localization to dendritic postsynaptic sites in developing hippocampal slices. Mol. Cell. Neurosci. 31, 37–51 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Shen, K., Teruel, M. N., Subramanian, K. & Meyer, T. CaMKIIβ functions as an F-actin targeting module that localizes CaMKIIα/β heterooligomers to dendritic spines. Neuron 21, 593–606 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Zhang, Y. P., Holbro, N. & Oertner, T. G. Optical induction of plasticity at single synapses reveals input-specific accumulation of αCaMKII. Proc. Natl Acad. Sci. USA 105, 12039–12044 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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. J. Neurosci. 24, 9324–9331 (2004). Using electron microscopy, this study shows that CaMKII translocation after LTP induction results in a persistent increase in CaMKII in the postsynaptic density.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Leonard, A. S., Lim, I. A., Hemsworth, D. E., Horne, M. C. & Hell, J. W. Calcium/calmodulin-dependent protein kinase II is associated with the N-methyl-D-aspartate receptor. Proc. Natl Acad. Sci. USA 96, 3239–3244 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Strack, S. & Colbran, R. J. Autophosphorylation-dependent targeting of calcium/ calmodulin-dependent protein kinase II by the NR2B subunit of the N-methyl-D-aspartate receptor. J. Biol. Chem. 273, 20689–20692 (1998). References 43 and 44 were the first studies to demonstrate that activated CaMKII binds to the NMDAR.

    Article  CAS  PubMed  Google Scholar 

  45. Bayer, K. U., De Koninck, P., Leonard, A. S., Hell, J. W. & Schulman, H. Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature 411, 801–805 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Strack, S., McNeill, R. B. & Colbran, R. J. 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. 275, 23798–23806 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Bayer, K. U. et al. Transition from reversible to persistent binding of CaMKII to postsynaptic sites and NR2B. J. Neurosci. 26, 1164–1174 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Robison, A. J., Bartlett, R. K., Bass, M. A. & Colbran, R. J. Differential modulation of Ca2+/calmodulin-dependent protein kinase II activity by regulated interactions with N-methyl-D-aspartate receptor NR2B subunits and α-actinin. J. Biol. Chem. 280, 39316–39323 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Barria, A. & Malinow, R. NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron 48, 289–301 (2005). A key paper demonstrating that the binding of CaMKII to the NMDAR is vital for LTP induction.

    Article  CAS  PubMed  Google Scholar 

  50. Foster, K. A. et al. Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation. J. Neurosci. 30, 2676–2685 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhou, Y. et al. Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning. J. Neurosci. 27, 13843–13853 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen, X. et al. Mass of the postsynaptic density and enumeration of three key molecules. Proc. Natl Acad. Sci. USA 102, 11551–11556 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shinohara, Y. et al. Left-right asymmetry of the hippocampal synapses with differential subunit allocation of glutamate receptors. Proc. Natl Acad. Sci. USA 105, 19498–19503 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sugiyama, Y., Kawabata, I., Sobue, K. & Okabe, S. Determination of absolute protein numbers in single synapses by a GFP-based calibration technique. Nature Methods 2, 677–684 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Walikonis, R. S. et al. Densin-180 forms a ternary complex with the α-subunit of Ca2+/calmodulin-dependent protein kinase II and α-actinin. J. Neurosci. 21, 423–433 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nikandrova, Y. A., Jiao, Y., Baucum, A. J., Tavalin, S. J. & Colbran, R. J. Ca2+/calmodulin-dependent protein kinase II binds to and phosphorylates a specific SAP97 splice variant to disrupt association with AKAP79/150 and modulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPAR) activity. J. Biol. Chem. 285, 923–934 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Krapivinsky, G., Medina, I., Krapivinsky, L., Gapon, S. & Clapham, D. E. SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron 43, 563–574 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Hudmon, A. et al. CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation. J. Cell Biol. 171, 537–547 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Welsby, P. J. et al. A mechanism for the direct regulation of T-type calcium channels by Ca2+/calmodulin-dependent kinase II. J. Neurosci. 23, 10116–10121 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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 105, 341–346 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Liu, X. Y. et al. Activity-dependent modulation of limbic dopamine D3 receptors by CaMKII. Neuron 61, 425–438 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hudmon, A. et al. A mechanism for Ca2+/calmodulin-dependent protein kinase II clustering at synaptic and nonsynaptic sites based on self-association. J. Neurosci. 25, 6971–6983 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Petersen, J. D. et al. Distribution of postsynaptic density (PSD)-95 and Ca2+/calmodulin-dependent protein kinase II at the PSD. J. Neurosci. 23, 11270–11278 (2003). This paper provides the best visualization to date of CaMKII within the PSD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Liao, D., Jones, A. & Malinow, R. Direct measurement of quantal changes underlying long-term potentiation in CA1 hippocampus. Neuron 9, 1089–1097 (1992).

    Article  CAS  PubMed  Google Scholar 

  65. Luthi, A. et al. Bi-directional modulation of AMPA receptor unitary conductance by synaptic activity. BMC Neurosci. 5, 44 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Poncer, J. C., Esteban, J. A. & Malinow, R. Multiple mechanisms for the potentiation of AMPA receptor-mediated transmission by α-Ca2+/calmodulin-dependent protein kinase II. J. Neurosci. 22, 4406–4411 (2002). A key demonstration of the multiple ways in which CaMKII can lead to synaptic strengthening.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Shi, S. H. et al. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284, 1811–1816 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Opazo, P. & Choquet, D. A three-step model for the synaptic recruitment of AMPA receptors. Mol. Cell. Neurosci. 46, 1–8 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Tomita, S., Stein, V., Stocker, T. J., Nicoll, R. A. & Bredt, D. S. Bidirectional synaptic plasticity regulated by phosphorylation of stargazin-like TARPs. Neuron 45, 269–277 (2005). The strongest evidence to date for the key role of CaMKII-dependent phosphorylation of stargazin in LTP.

    Article  CAS  PubMed  Google Scholar 

  70. Opazo, P. et al. CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron 67, 239–252 (2010). This paper tracks single AMPA channels and provides the first visualization of the trapping of the AMPAR at the synapse. The role of CaMKII-dependent phosphorylation of stargazin in this process is confirmed.

    Article  CAS  PubMed  Google Scholar 

  71. Barria, A., Derkach, V. & Soderling, T. Identification of the Ca2+/calmodulin-dependent protein kinase II regulatory phosphorylation site in the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-type glutamate receptor. J. Biol. Chem. 272, 32727–32730 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Roche, K. W., O'Brien, R. J., Mammen, A. L., Bernhardt, J. & Huganir, R. L. Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16, 1179–1188 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Lu, W., Isozaki, K., Roche, K. W. & Nicoll, R. A. Synaptic targeting of AMPA receptors is regulated by a CaMKII site in the first intracellular loop of GluA1. Proc. Natl Acad. Sci. USA 107, 22266–22271 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Banke, T. G. et al. Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J. Neurosci. 20, 89–102 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Boehm, J. et al. Synaptic incorporation of AMPA receptors during LTP is controlled by a PKC phosphorylation site on GluR1. Neuron 51, 213–225 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Lee, H. K., Barbarosie, M., Kameyama, K., Bear, M. F. & Huganir, R. L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Barria, A., Muller, D., Derkach, V., Griffith, L. C. & Soderling, T. R. Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. Science 276, 2042–2045 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Kristensen, A. S. et al. Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating. Nature Neurosci. 14, 727–735 (2011). This paper resolves a problem that the field had been struggling with: under what conditions does CaMKII-dependent phosphorylation of GluR1 enhance channel conductance? It is shown that this form of regulation requires the presence of stargazin.

    Article  CAS  PubMed  Google Scholar 

  79. Derkach, V. A., Oh, M. C., Guire, E. S. & Soderling, T. R. Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nature Rev. Neurosci. 8, 101–113 (2007).

    Article  CAS  Google Scholar 

  80. Lee, H. K., Takamiya, K., He, K., Song, L. & Huganir, R. L. Specific roles of AMPA receptor subunit GluR1 (GluA1) phosphorylation sites in regulating synaptic plasticity in the CA1 region of hippocampus. J. Neurophysiol. 103, 479–489 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Andrasfalvy, B. K. & Magee, J. C. Changes in AMPA receptor currents following LTP induction on rat CA1 pyramidal neurones. J. Physiol. 559, 543–554 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Vinade, L. & Dosemeci, A. Regulation of the phosphorylation state of the AMPA receptor GluR1 subunit in the postsynaptic density. Cell. Mol. Neurobiol. 20, 451–463 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Tsui, J. & Malenka, R. C. Substrate localization creates specificity in calcium/calmodulin-dependent protein kinase II signaling at synapses. J. Biol. Chem. 281, 13794–13804 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Yudowski, G. A., Puthenveedu, M. A. & von Zastrow, M. Distinct modes of regulated receptor insertion to the somatodendritic plasma membrane. Nature Neurosci. 9, 622–627 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Makino, H. & Malinow, R. AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64, 381–390 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Patterson, M. A., Szatmari, E. M. & Yasuda, R. AMPA receptors are exocytosed in stimulated spines and adjacent dendrites in a Ras-ERK-dependent manner during long-term potentiation. Proc. Natl Acad. Sci. USA 107, 15951–15956 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Park, M., Penick, E. C., Edwards, J. G., Kauer, J. A. & Ehlers, M. D. Recycling endosomes supply AMPA receptors for LTP. Science 305, 1972–1975 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Park, M. et al. Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52, 817–830 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wang, Z. et al. Myosin Vb mobilizes recycling endosomes and AMPA receptors for postsynaptic plasticity. Cell 135, 535–548 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kennedy, M. J., Davison, I. G., Robinson, C. G. & Ehlers, M. D. Syntaxin-4 defines a domain for activity-dependent exocytosis in dendritic spines. Cell 141, 524–535 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lledo, P. M., Zhang, X., Sudhof, T. C., Malenka, R. C. & Nicoll, R. A. Postsynaptic membrane fusion and long-term potentiation. Science 279, 399–403 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Yang, Y., Wang, X. B., Frerking, M. & Zhou, Q. Spine expansion and stabilization associated with long-term potentiation. J. Neurosci. 28, 5740–5751 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. English, J. D. & Sweatt, J. D. A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J. Biol. Chem. 272, 19103–19106 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Zhu, J., Qin, Y., Zhao, M., Van Aelst, L. & Malinow, R. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110, 443–455 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Cullen, P. J. & Lockyer, P. J. Integration of calcium and Ras signalling. Nature Rev. Mol. Cell. Biol. 3, 339–348 (2002).

    Article  CAS  Google Scholar 

  96. Kim, C. H. et al. Persistent hippocampal CA1 LTP in mice lacking the C-terminal PDZ ligand of GluR1. Nature Neurosci. 8, 985–987 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Schnell, E. et al. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc. Natl Acad. Sci. USA 99, 13902–13907 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bats, C., Groc, L. & Choquet, D. The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking. Neuron 53, 719–734 (2007). References 97 and 98 provide the key evidence for the role of stargazin interaction with PSD95 in anchoring AMPARs at the synapse.

    Article  CAS  PubMed  Google Scholar 

  99. Ehrlich, I. & Malinow, R. Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. J. Neurosci. 24, 916–927 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sainlos, M. et al. Biomimetic divalent ligands for the acute disruption of synaptic AMPAR stabilization. Nature Chem. Biol. 7, 81–91 (2011).

    Article  CAS  Google Scholar 

  101. Kim, C. H. & Lisman, J. E. A labile component of AMPA receptor-mediated synaptic transmission is dependent on microtubule motors, actin, and N-ethylmaleimide-sensitive factor. J. Neurosci. 21, 4188–4194 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sanhueza, M., McIntyre, C. C. & Lisman, J. E. Reversal of synaptic memory by Ca2+/calmodulin-dependent protein kinase II inhibitor. J. Neurosci. 27, 5190–5199 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chen, X. et al. PSD-95 is required to sustain the molecular organization of the postsynaptic density. J. Neurosci. 31, 6329–6338 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Dani, A., Huang, B., Bergan, J., Dulac, C. & Zhuang, X. Superresolution imaging of chemical synapses in the brain. Neuron 68, 843–856 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lengyel, I. et al. Autonomous activity of CaMKII is only transiently increased following the induction of long-term potentiation in the rat hippocampus. Eur. J. Neurosci. 20, 3063–3072 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Murakoshi, H., Wang, H. & Yasuda, R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature 472, 100–104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Vest, R. S., Davies, K. D., O'Leary, H., Port, J. D. & Bayer, K. U. Dual mechanism of a natural CaMKII inhibitor. Mol. Biol. Cell 18, 5024–5033 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sanhueza, M. et al. Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength. J. Neurosci. 31, 9170–9178 (2011). The elucidation of the molecular basis of memory requires the demonstration that if a putative memory mechanism is attacked, saturated LTP can be reversed. Furthermore, it should then be possible to re-induce LTP. This paper shows that these criteria can be met using CN compounds, which reduce the amount of CaMKII–NMDAR complex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Otmakhov, N., Griffith, L. C. & Lisman, J. E. Postsynaptic inhibitors of calcium/calmodulin-dependent protein kinase type II block induction but not maintenance of pairing-induced long-term potentiation. J. Neurosci. 17, 5357–5365 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tsien, R. W., Schulman, H. & Malinow, R. Peptide inhibitors of PKC and CaMK block induction but not expression of long-term potentiation. Adv. Second Messenger Phosphoprotein Res. 24, 101–107 (1990).

    CAS  PubMed  Google Scholar 

  111. Buard, I. et al. CaMKII “autonomy” is required for initiating but not for maintaining neuronal long-term information storage. J. Neurosci. 30, 8214–8220 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ostroff, L. E., Fiala, J. C., Allwardt, B. & Harris, K. M. Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices. Neuron 35, 535–545 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Tanaka, J. I. et al. Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319, 1683–1687 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Smith, W. B., Starck, S. R., Roberts, R. W. & Schuman, E. M. Dopaminergic stimulation of local protein synthesis enhances surface expression of GluR1 and synaptic transmission in hippocampal neurons. Neuron 45, 765–779 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Lisman, J. Memory erasure by very high concentrations of ZIP may not be due to PKM-zeta. Hippocampus 28 Sep 2011 (doi:10.1002/hipo.20980).

    Article  CAS  PubMed  Google Scholar 

  116. Frey, U. & Morris, R. G. Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci. 21, 181–188 (1998).

    Article  CAS  PubMed  Google Scholar 

  117. Schuman, E. M., Dynes, J. L. & Steward, O. Synaptic regulation of translation of dendritic mRNAs. J. Neurosci. 26, 7143–7146 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bramham, C. R., Worley, P. F., Moore, M. J. & Guzowski, J. F. The immediate early gene arc/arg3.1: regulation, mechanisms, and function. J. Neurosci. 28, 11760–11767 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Day, J. J. & Sweatt, J. D. Cognitive neuroepigenetics: a role for epigenetic mechanisms in learning and memory. Neurobiol. Learn. Mem. 96, 2–12 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Miller, S. et al. Disruption of dendritic translation of CaMKIIα impairs stabilization of synaptic plasticity and memory consolidation. Neuron 36, 507–519 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Pepke, S., Kinzer-Ursem, T., Mihalas, S. & Kennedy, M. B. A dynamic model of interactions of Ca2+, calmodulin, and catalytic subunits of Ca2+/calmodulin-dependent protein kinase II. PLoS Comput. Biol. 6, e1000675 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Byrne, M. J., Putkey, J. A., Waxham, M. N. & Kubota, Y. Dissecting cooperative calmodulin binding to CaM kinase II: a detailed stochastic model. J. Comput. Neurosci. 27, 621–638 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Huang, K. P. et al. Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. J. Neurosci. 24, 10660–10669 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhabotinsky, A. M., Camp, R. N., Epstein, I. R. & Lisman, J. E. Role of the neurogranin concentrated in spines in the induction of long-term potentiation. J. Neurosci. 26, 7337–7347 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hanson, P. I. & Schulman, H. Inhibitory autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase analyzed by site-directed mutagenesis. J. Biol. Chem. 267, 17216–17224 (1992).

    CAS  PubMed  Google Scholar 

  126. Coultrap, S. J., Buard, I., Kulbe, J. R., Dell'Acqua, M. L. & Bayer, K. U. CaMKII autonomy is substrate-dependent and further stimulated by Ca2+/calmodulin. J. Biol. Chem. 285, 17930–17937 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Jama, A. M., Fenton, J., Robertson, S. D. & Torok, K. Time-dependent autoinactivation of phospho-Thr286-αCa2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 284, 28146–28155 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Pi, H. J., Otmakhov, N., Lemelin, D., De Koninck, P. & Lisman, J. Autonomous CaMKII can promote either long-term potentiation or long-term depression, depending on the state of T305/T306 phosphorylation. J. Neurosci. 30, 8704–8709 (2010). The surprising complexity of CaMKII regulation of synaptic strength is demonstrated in this paper. Notably, if T305 and T306 phosphorylation is allowed to occur, activated CaMKII promotes LTD rather than LTP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Elgersma, Y. et al. Inhibitory autophosphorylation of CaMKII controls PSD association, plasticity, and learning. Neuron 36, 493–505 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Weeber, E. J. et al. Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J. Neurosci. 23, 2634–2644 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Skelding, K. A. et al. Regulation of CaMKII by phospho-Thr253 or phospho-Thr286 sensitive targeting alters cellular function. Cell. Signal. 22, 759–769 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Gurd, J. W. et al. Ischemia and status epilepitcus result in enhanced phosphorylation of calcium and calmodulin-stimulated protein kinase II on threonine 253. Brain Res. 1218, 158–165 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. Marsden, K. C., Shemesh, A., Bayer, K. U. & Carroll, R. C. Selective translocation of Ca2+/calmodulin protein kinase IIα (CaMKIIα) to inhibitory synapses. Proc. Natl Acad. Sci. USA 107, 20559–20564 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sacktor, T. C. How does PKMζ maintain long-term memory? Nature Rev. Neurosci. 12, 9–15 (2011).

    Article  CAS  Google Scholar 

  135. Shema, R. et al. Enhancement of consolidated long-term memory by overexpression of protein kinase Mζ in the neocortex. Science 331, 1207–1210 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Sacktor, T. C. & Fenton, A. A. Appropriate application of ZIP for PKMζ inhibition, LTP reversal, and memory erasure. Hippocampus 4 Oct 2011 (doi:10.1002/hipo.20978).

    Article  CAS  PubMed  Google Scholar 

  137. Volk, L. J., Bachman, J., Johnson, R. C., Yu, Y. & Huganir, R. L. Insights into synaptic plasticity and memory maintenance from the protein kinase C ζ knockout mouse. Soc. Neurosci. Abstr. 238.06 (Washington DC, 13 Nov 2011).

  138. Miller, P., Zhabotinsky, A. M., Lisman, J. E. & Wang, X. J. The stability of a stochastic CaMKII switch: dependence on the number of enzyme molecules and protein turnover. PLoS Biol. 3, e107 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mullasseril, P., Dosemeci, A., Lisman, J. E. & Griffith, L. C. A structural mechanism for maintaining the 'on-state' of the CaMKII memory switch in the post-synaptic density. J. Neurochem. 103, 357–364 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Cheriyan, J., Kumar, P., Mayadevi, M., Surolia, A. & Omkumar, R. V. Calcium/calmodulin dependent protein kinase II bound to NMDA receptor 2B subunit exhibits increased ATP affinity and attenuated dephosphorylation. PLoS ONE 6, e16495 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Irvine, E. E. et al. Properties of contextual memory formed in the absence of αCaMKII autophosphorylation. Mol. Brain 4, 8 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Radwanska, K. et al. Mechanism for long-term memory formation when synaptic strengthening is impaired. Proc. Natl Acad. Sci. USA 108, 18471–18475 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Bingol, B. et al. Autophosphorylated CaMKIIα acts as a scaffold to recruit proteasomes to dendritic spines. Cell 140, 567–578 (2010). One reason for the multi-subunit structure of CaMKII may be that it serves as a docking site for many other proteins, localizing them to the synapse. This paper points strongly in that direction.

    Article  CAS  PubMed  Google Scholar 

  144. Atkins, C. M., Nozaki, N., Shigeri, Y. & Soderling, T. R. Cytoplasmic polyadenylation element binding protein-dependent protein synthesis is regulated by calcium/calmodulin-dependent protein kinase II. J. Neurosci. 24, 5193–5201 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Fonseca, R., Vabulas, R. M., Hartl, F. U., Bonhoeffer, T. & Nagerl, U. V. A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP. Neuron 52, 239–245 (2006).

    Article  CAS  PubMed  Google Scholar 

  146. Hoelz, A., Nairn, A. C. & Kuriyan, J. Crystal structure of a tetradecameric assembly of the association domain of Ca2+/calmodulin-dependent kinase II. Mol. Cell 11, 1241–1251 (2003).

    Article  CAS  PubMed  Google Scholar 

  147. Rosenberg, O. S., Deindl, S., Sung, R. J., Nairn, A. C. & Kuriyan, J. Structure of the autoinhibited kinase domain of CaMKII and SAXS analysis of the holoenzyme. Cell 123, 849–860 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. Kolodziej, S. J., Hudmon, A., Waxham, M. N. & Stoops, J. K. Three-dimensional reconstructions of calcium/calmodulin-dependent (CaM) kinase IIα and truncated CaM kinase IIα reveal a unique organization for its structural core and functional domains. J. Biol. Chem. 275, 14354–14359 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Morris, E. P. & Torok, K. Oligomeric structure of α-calmodulin-dependent protein kinase II. J. Mol. Biol. 308, 1–8 (2001).

    Article  CAS  PubMed  Google Scholar 

  150. Rellos, P. et al. Structure of the CaMKIIδ/calmodulin complex reveals the molecular mechanism of CaMKII kinase activation. PLoS Biol. 8, e1000426 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Bradshaw, J. M., Kubota, Y., Meyer, T. & Schulman, H. An ultrasensitive Ca2+/calmodulin-dependent protein kinase II-protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling. Proc. Natl Acad. Sci. USA 100, 10512–10517 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Gaertner, T. R. et al. Comparative analyses of the three-dimensional structures and enzymatic properties of α, β, γ, and δ isoforms of Ca2+-calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 12484–12494 (2004).

    Article  CAS  PubMed  Google Scholar 

  153. Svoboda, K., Tank, D. W. & Denk, W. Direct measurement of coupling between dendritic spines and shafts. Science 272, 716–719 (1996). The localization of the biochemistry of LTP to the activated spine is strongly dependent on diffusion restriction that is a consequence of the narrow spine neck. This paper provides quantification of that restriction.

    Article  CAS  PubMed  Google Scholar 

  154. Harvey, C. D., Yasuda, R., Zhong, H. & Svoboda, K. The spread of Ras activity triggered by activation of a single dendritic spine. Science 321, 136–140 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Lisman, J. & Raghavachari, S. A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Sci. STKE. 2006, re11 (2006).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank P. De Koninck, W. Ross and N. Otmakhov for comments on this Review. We especially thank L. Chao for discussion about CaMKII structure and for preparing the figures for Box 1. We gratefully acknowledge the support of the Ellison Foundation, the US National Institutes of Health (grant R01 DA027807) and the 2011 Marine Biological Laboratory Research Award.

Author information

Authors and Affiliations

  1. Department of Biology, Brandeis University, Waltham, 02454, Massachusetts, USA

    John Lisman

  2. Department of Neurobiology, Duke University, Durham, 27710, North Carolina, USA

    Ryohei Yasuda & Sridhar Raghavachari

Authors
  1. John Lisman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryohei Yasuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sridhar Raghavachari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John Lisman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

John Lisman's homepage

Glossary

Two-photon glutamate uncaging

This technique involves focusing a pulsed laser beam into a solution that includes caged glutamate. The glutamate is released into the diffraction-limited volume when photolysis of the caged molecules by a two-photon excitation process occurs at the focus.

Two-photon fluorescence lifetime imaging

(2pFLIM). The fluorescence lifetime can be determined by measuring fluorescence decay (which occurs over a period of nanoseconds) after a short pulse of fluorescence excitation. Probes can be made in which the lifetime changes with the conformation of the protein, thereby providing a measure of its activation state.

Hebbian condition

The Hebb rule indicates that for long-term synaptic strengthening of excitatory synapses to occur, two conditions must be met: the presynaptic input at that synapse must be active and the postsynaptic neuron must be strongly depolarized by multiple excitatory inputs.

Calcium nanodomain

A region that extends a few tens of nanometres from a calcium-permeable channel and where calcium ions that have come through the channel are at a high concentration. Intracellular signalling is affected by the positioning of calcium sensors within the nanodomain.

Postsynaptic density

(PSD). A structure, rich in scaffolding proteins and enzymes, that is attached to the postsynaptic membrane.

CN compounds

Peptides that are derived from an endogenous protein that inhibits calcium/calmodulin-dependent protein kinase II.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lisman, J., Yasuda, R. & Raghavachari, S. Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci 13, 169–182 (2012). https://doi.org/10.1038/nrn3192

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3192

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing