Review Article | Published:

The molecular basis of CaMKII function in synaptic and behavioural memory

Nature Reviews Neurosciencevolume 3pages175190 (2002) | Download Citation



Long-term potentiation (LTP) in the CA1 region of the hippocampus has been the primary model by which to study the cellular and molecular basis of memory. Calcium/calmodulin-dependent protein kinase II (CaMKII) is necessary for LTP induction, is persistently activated by stimuli that elicit LTP, and can, by itself, enhance the efficacy of synaptic transmission. The analysis of CaMKII autophosphorylation and dephosphorylation indicates that this kinase could serve as a molecular switch that is capable of long-term memory storage. Consistent with such a role, mutations that prevent persistent activation of CaMKII block LTP, experience-dependent plasticity and behavioural memory. These results make CaMKII a leading candidate in the search for the molecular basis of memory.

Key Points

  • Calcium/calmodulin-dependent protein kinase II (CaMKII) — the main protein of the postsynaptic density — is a Ca2+/calmodulin-activated dodecameric enzyme. One of its main functional properties is its ability to phosphorylate itself. This reaction alters the enzyme such that its activity becomes independent of Ca2+/calmodulin. This property makes CaMKII a good candidate for the storage of long-term synaptic memory.

  • The analysis of long-term potentiation (LTP) has provided the deepest insights into CaMKII function in synaptic physiology. So, CaMKII is activated by Ca2+ entry through the NMDA receptor, and pharmacological and genetic results have shown that CaMKII is necessary and sufficient for the induction of LTP.

  • CaMKII translocates to synapses and binds directly to the NMDA receptor. Like autophosphorylation, this interaction reduces the dependence of CaMKII on Ca2+/calmodulin. CaMKII translocation places it in an ideal situation to control synaptic strength, largely by affecting the functional properties of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, as well as their trafficking and anchoring to the postsynaptic membrane.

  • CaMKII might act as a bistable switch for the long-term storage of synaptic memory. The newest model in this regard takes into account not only the biochemical properties of the enzyme, but also the specific environment that it encounters in the postsynaptic density. Biochemical, pharmacological and electrophysiological data lend support to the model, although definitive proof of its validity is still missing.

  • Progress has been made in understanding how CaMKII contributes to brain function at the systems level. So, eliminating CaMKII phosphorylation interferes with activity-dependent developmental processes and experience-dependent plasticity in vivo. Behavioural tests also show that memory is strongly impaired by interfering with CaMKII function.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Soderling, T. R., Chang, B. & Brickey, D. Cellular signaling through multifunctional Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 276, 3719–3722 (2001).

  2. 2

    Hudmon, A. & Schulman, H. Neuronal Ca2+/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function. Annu. Rev. Biochem. 2002 (10.1146/annurev.biochem.71.110601.135410).

  3. 3

    Lisman, J. The CaM kinase II hypothesis for the storage of synaptic memory. Trends Neurosci. 17, 406–412 (1994).

  4. 4

    Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

  5. 5

    Malenka, R. C. & Nicoll, R. A. Long-term potentiation — a decade of progress? Science 285, 1870–1874 (1999).Summarizes extensive work that points to a postsynaptic site for the expression of LTP in the CA1 pyramidal cells of the hippocampus.

  6. 6

    Rich, R. C. & Schulman, H. Substrate-directed function of calmodulin in autophosphorylation of Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 273, 28424–28429 (1998).

  7. 7

    Yang, E. & Schulman, H. Structural examination of autoregulation of multifunctional calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 274, 26199–26208 (1999).

  8. 8

    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).Shows that autophosphorylation of purified CaMKII confers Ca2+-independent activity to the enzyme.

  9. 9

    Lou, L. L., Lloyd, S. J. & Schulman, H. Activation of the multifunctional Ca2+/calmodulin-dependent protein kinase by autophosphorylation: ATP modulates production of an autonomous enzyme. Proc. Natl Acad. Sci. USA 83, 9497–9501 (1986).

  10. 10

    Saitoh, T. & Schwartz, J. H. Phosphorylation-dependent subcellular translocation of a Ca2+/calmodulin-dependent protein kinase produces an autonomous enzyme in Aplysia neurons. J. Cell. Biol. 100, 835–842 (1985).The first indication that CaMKII can be autonomous.

  11. 11

    Woodgett, J. R., Davison, M. T. & Cohen, P. The calmodulin-dependent glycogen synthase kinase from rabbit skeletal muscle. Purification, subunit structure and substrate specificity. Eur. J. Biochem. 136, 481–487 (1983).

  12. 12

    Kanaseki, T., Ikeuchi, Y., Sugiura, H. & Yamauchi, T. Structural features of Ca2+/calmodulin-dependent protein kinase II revealed by electron microscopy. J. Cell. Biol. 115, 1049–1060 (1991).

  13. 13

    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).

  14. 14

    Molloy, S. S. & Kennedy, M. B. Autophosphorylation of type II Ca2+/calmodulin-dependent protein kinase in cultures of postnatal rat hippocampal slices. Proc. Natl Acad. Sci. USA 88, 4756–4760 (1991).

  15. 15

    De Koninck, P. & Schulman, H. Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Science 279, 227–230 (1998).

  16. 16

    Petersen, C. C., Malenka, R. C., Nicoll, R. A. & Hopfield, J. J. All-or-none potentiation at CA3–CA1 synapses. Proc. Natl Acad. Sci. USA 95, 4732–4737 (1998).The only report, so far, of synaptic plasticity at a single hippocampal synapse. It shows that plasticity occurs as a large and discrete change, supporting the idea that a switch-like process controls plasticity.

  17. 17

    Fukunaga, K., Stoppini, L., Miyamoto, E. & Muller, D. Long-term potentiation is associated with an increased activity of Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 268, 7863–7867 (1993).Shows that LTP produces a persistent activation of CaMKII.

  18. 18

    Fukunaga, K., Muller, D. & Miyamoto, E. Increased phosphorylation of Ca2+/calmodulin-dependent protein kinase II and its endogenous substrates in the induction of long-term potentiation. J. Biol. Chem. 270, 6119–6124 (1995).

  19. 19

    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).An elegant study showing changes in CaMKII during LTP and consequent changes in AMPA receptors.

  20. 20

    Ouyang, Y., Kantor, D., Harris, K. M., Schuman, E. M. & Kennedy, M. B. Visualization of the distribution of autophosphorylated calcium/calmodulin-dependent protein kinase II after tetanic stimulation in the CA1 area of the hippocampus. J. Neurosci. 17, 5416–5427 (1997).

  21. 21

    Ouyang, Y., Rosenstein, A., Kreiman, G., Schuman, E. M. & Kennedy, M. B. Tetanic stimulation leads to increased accumulation of Ca2+/calmodulin-dependent protein kinase II via dendritic protein synthesis in hippocampal neurons. J. Neurosci. 19, 7823–7833 (1999).

  22. 22

    Jaffe, D. B. et al. The spread of Na+ spikes determines the pattern of dendritic Ca2+ entry into hippocampal neurons. Nature 357, 244–246 (1992).

  23. 23

    Inagaki, N. et al. Activation of Ca2+/calmodulin-dependent protein kinase II within post-synaptic dendritic spines of cultured hippocampal neurons. J. Biol. Chem. 275, 27165–27171 (2000).

  24. 24

    Gardoni, F. et al. Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor. J. Neurosci. 21, 1501–1509 (2001).

  25. 25

    Strack, S., Choi, S., Lovinger, D. M. & Colbran, R. J. Translocation of autophosphorylated calcium/calmodulin-dependent protein kinase II to the postsynaptic density. J. Biol. Chem. 272, 13467–13470 (1997).Shows a persistent translocation of CaMKII to the PSD after chemically induced LTP. By contrast, translocation is rapidly reversible after stimulation protocols that do not induce potentiation. This paper further shows that CaMKII binding to the PSD inhibits the ability of PP2A to dephosphorylate the kinase.

  26. 26

    Malinow, R., Schulman, H. & Tsien, R. W. Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science 245, 862–866 (1989).

  27. 27

    Tokumitsu, H. et al. KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 265, 4315–4320 (1990).

  28. 28

    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).

  29. 29

    Silva, A. J., Stevens, C. F., Tonegawa, S. & Wang, Y. Deficient hippocampal long-term potentiation in α-calcium-calmodulin kinase II mutant mice. Science 257, 201–206 (1992).

  30. 30

    Hinds, H. L., Tonegawa, S. & Malinow, R. CA1 long-term potentiation is diminished but present in hippocampal slices from α-CaMKII mutant mice. Learn. Mem. 5, 344–354 (1998).

  31. 31

    Giese, K. P., Fedorov, N. B., Filipkowski, R. K. & Silva, A. J. Autophosphorylation at Thr286 of the α-calcium-calmodulin kinase II in LTP and learning. Science 279, 870–873 (1998).Shows the powerful physiological and behavioural effects of a single amino-acid change in CaMKII that prevents Thr286 phosphorylation.

  32. 32

    Klann, E. Chen, S. J. & Sweatt, J. D. Persistent protein kinase activation in the maintenance phase of long-term potentiation. J. Biol. Chem. 266, 24253–24256 (1991).

  33. 33

    Kleschevnikov, A. M. & Routtenberg, A. PKC activation rescues LTP from NMDA receptor blockade. Hippocampus 11, 168–175 (2001)

  34. 34

    Hrabetova, S. & Sacktor, T. C. Bidirectional regulation of protein kinase Mα in the maintenance of long-term potentiation and long–term depression. J. Neurosci. 16, 5324–5333 (1996).

  35. 35

    Davies, S. N., Lester, R. A., Reymann, K. G. & Collingridge, G. L. Temporally distinct pre- and post-synaptic mechanisms maintain long-term potentiation. Nature 338, 500–503 (1989).

  36. 36

    Montgomery, J. M., Pavlidis, P. & Madison, D. V. Pair recordings reveal all-silent synaptic connections and the postsynaptic expression of long-term potentiation. Neuron 29, 691–701 (2001).

  37. 37

    McGlade-McCulloh, E., Yamamoto, H., Tan, S. E., Brickey, D. A. & Soderling, T. R. Phosphorylation and regulation of glutamate receptors by calcium/calmodulin-dependent protein kinase II. Nature 362, 640–642 (1993).

  38. 38

    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).A classic paper that shows the close correspondence of LTP to the potentiation that can be produced by CaMKII.

  39. 39

    Pettit, D. L., Perlman, S. & Malinow, R. Potentiated transmission and prevention of further LTP by increased CaMKII activity in postsynaptic hippocampal slice neurons. Science 266, 1881–1885 (1994).

  40. 40

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

  41. 41

    Manabe, T., Renner, P. & Nicoll, R. A. Postsynaptic contribution to long-term potentiation revealed by the analysis of miniature synaptic currents. Nature 355, 50–55 (1992).

  42. 42

    Liao, D., Hessler, N. A. & Malinow, R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375, 400–404 (1995).The first clear demonstration of synapses that have an NMDA receptor component but lack an AMPA receptor component. Led to subsequent work showing that CaMKII can direct the addition of AMPA channels to synapses.

  43. 43

    Shen, K. & Meyer, T. Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. Science 284, 162–166 (1999).

  44. 44

    Dosemeci, A. et al. Glutamate-induced transient modification of the postsynaptic density. Proc. Natl Acad. Sci. USA 98, 10428–10432 (2001).

  45. 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).Provides a biochemical basis for the translocation of CaMKII to the NMDA receptor, and shows that binding locks the kinase in an autonomous state.

  46. 46

    Gardoni, F. et al. Calcium/calmodulin-dependent protein kinase II is associated with NR2A/B subunits of NMDA receptor in postsynaptic densities. J. Neurochem. 71, 1733–1741 (1998).

  47. 47

    Strack, S., Robison, A. J., Bass, M. A. & Colbran, R. J. Association of calcium/calmodulin-dependent kinase II with developmentally regulated splice variants of the postsynaptic density protein densin-180. J. Biol. Chem. 275, 25061–25064 (2000).

  48. 48

    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).

  49. 49

    Shen, K., Teruel, M. N., Connor, J. H., Shenolikar, S. & Meyer, T. Molecular memory by reversible translocation of calcium/calmodulin-dependent protein kinase II. Nature Neurosci. 3, 881–886 (2000).

  50. 50

    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).

  51. 51

    Yoshimura, Y. & Yamauchi, T. Phosphorylation-dependent reversible association of Ca2+/calmodulin-dependent protein kinase II with the postsynaptic densities. J. Biol. Chem. 272, 26354–26359 (1997).

  52. 52

    Rostas, J. A., Kavanagh, J. M., Dodd, P. R., Heath, J. W. & Powis, D. A. Mechanisms of synaptic plasticity. Changes in postsynaptic densities and glutamate receptors in chicken forebrain during maturation. Mol. Neurobiol. 5, 203–216 (1991).

  53. 53

    Scheetz, A. J., Prusky, G. T. & Constantine-Paton, M. Chronic NMDA receptor antagonism during retinotopic map formation depresses CaM kinase II differentiation in rat superior colliculus. Eur. J. Neurosci. 8, 1322–1328 (1996).

  54. 54

    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).

  55. 55

    Mammen, A. L., Kameyama, K., Roche, K. W. & Huganir, R. L. Phosphorylation of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II. J. Biol. Chem. 272, 32528–32533 (1997).

  56. 56

    Derkach, V., Barria, A. & Soderling, T. R. Ca2+/calmodulin-kinase II enhances channel conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc. Natl Acad. Sci. USA 96, 3269–3274 (1999).

  57. 57

    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).Shows how the phosphorylation state of different sites on GluR1 changes during LTP, depotentiation, LTD and the reversal of LTD.

  58. 58

    Benke, T. A., Luthi, A., Isaac, J. T. & Collingridge, G. L. Modulation of AMPA receptor unitary conductance by synaptic activity. Nature 393, 793–797 (1998).

  59. 59

    Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000).

  60. 60

    Nusser, Z. et al. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21, 545–559 (1998).

  61. 61

    Wu, G., Malinow, R. & Cline, H. T. Maturation of a central glutamatergic synapse. Science 274, 972–976 (1996).The first in vivo demonstration of silent synapses and their maturation by the addition of AMPA-receptor-mediated responses through a CaMKII-dependent mechanism.

  62. 62

    Chen, L. et al. Stargazing regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000).

  63. 63

    Passafaro, M., Piech, V. & Sheng, M. Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons. Nature Neurosci. 4, 917–926 (2001).

  64. 64

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

  65. 65

    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).

  66. 66

    Shi, S., Hayashi, Y., Esteban, J. A. & Malinow, R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331–343 (2001).This study uses elegant molecular-biological and electrophysiological tools to determine some of the molecular constraints that govern the delivery of AMPA receptors to hippocampal synapses.

  67. 67

    Maletic-Savatic, M., Koothan, T. & Malinow, R. Calcium-evoked dendritic exocytosis in cultured hippocampal neurons. Part II: mediation by calcium/calmodulin-dependent protein kinase II. J. Neurosci. 18, 6814–6821 (1998).

  68. 68

    Liao, D., Scannevin, R. H. & Huganir, R. Activation of silent synapses by rapid activity-dependent synaptic recruitment of AMPA receptors. J. Neurosci. 21, 6008–6017 (2001).

  69. 69

    Lisman, J. E. & Zhabotinsky, A. M. A model of synaptic memory: a CaMKII/PP1 switch that potentiates transmission by organizing an AMPA receptor anchoring assembly. Neuron 31, 191–201 (2001).The most recent model of how CaMKII/PP1 interactions in the PSD could form a bistable switch capable of long-term information storage. Suggests how CaMKII bound to the NMDA channel could organize an assembly capable of anchoring additional AMPA channels at the synapse.

  70. 70

    Allison, D. W., Gelfand, V. I., Spector, I. & Craig, A. M. Role of actin in anchoring postsynaptic receptors in cultured hippocampal neurons: differential attachment of NMDA versus AMPA receptors. J. Neurosci. 18, 2423–2436 (1998).

  71. 71

    Kim, C. H. & Lisman, J. E. A role of actin filament in synaptic transmission and long-term potentiation. J. Neurosci. 19, 4314–4324 (1999).

  72. 72

    Lisman, J. E. & McIntyre, C. C. Synaptic plasticity: a molecular memory switch. Curr. Biol. 11, R788–R791 (2001).

  73. 73

    O'Dell, T. & Kandel, E. Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases. Learn. Mem. 1, 129–139 (1994).

  74. 74

    Sheng, M. & Lee, S. H. AMPA receptor trafficking and the control of synaptic transmission. Cell 105, 825–828 (2001).

  75. 75

    Holmes, W. R. Models of calmodulin trapping and CaM kinase II activation in a dendritic spine. J. Comput. Neurosci. 8, 65–85 (2000).

  76. 76

    Crick, F. Memory and molecular turnover. Nature 312, 101 (1984).

  77. 77

    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).

  78. 78

    Lisman, J. E. & Goldring, M. A. Feasibility of long-term storage of graded information by the Ca2+/calmodulin-dependent protein kinase molecules of the postsynaptic density. Proc. Natl Acad. Sci. USA 85, 5320–5324 (1988).

  79. 79

    Zhabotinsky, A. M. Bistability in the Ca2+/calmodulin-dependent protein kinase-phosphatase system. Biophys. J. 79, 2211–2221 (2000).

  80. 80

    Strack, S., Barban, M. A., Wadzinski, B. E. & Colbran, R. J. Differential inactivation of postsynaptic density-associated and soluble Ca2+/calmodulin-dependent protein kinase II by protein phosphatases 1 and 2A. J. Neurochem. 68, 2119–2128 (1997).

  81. 81

    Yoshimura, Y., Sogawa, Y. & Yamauchi, T. Protein phosphatase 1 is involved in the dissociation of Ca2+/calmodulin-dependent protein kinase II from postsynaptic densities. FEBS Lett. 446, 239–242 (1999).

  82. 82

    Watanabe, T. et al. Protein phosphatase 1 regulation by inhibitors and targeting subunits. Proc. Natl Acad. Sci. USA 98, 3080–3085 (2001).

  83. 83

    Sedman, G. L., Jeffrey, P. L., Austin, L. & Rostas, J. A. The metabolic turnover of the major proteins of the postsynaptic density. Brain Res. 387, 221–230 (1986).

  84. 84

    Huang, C. C., Liang, Y. C. & Hsu, K. S. Characterization of the mechanism underlying the reversal of long-term potentiation by low-frequency stimulation at hippocampal CA1 synapses. J. Biol. Chem. 276, 48108–48117 (2001).

  85. 85

    Feng, T. P. The involvement of PKC and multifunctional CaM kinase II of the postsynaptic neuron in induction and maintenance of long-term potentiation. Prog. Brain Res. 105, 55–63 (1995).

  86. 86

    Gardoni, F., Bellone, C., Cattabeni, F. & Di Luca, M. Protein kinase C activation modulates α-calmodulin kinase II binding to NR2A subunit of N-methyl-d-aspartate receptor complex. J. Biol. Chem. 276, 7609–7613 (2001).

  87. 87

    Frey, U., Krug, M., Reymann, K. G. & Matthies, H. Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro. Brain Res. 452, 57–65 (1988).

  88. 88

    Frey, U., Huang, Y. Y. & Kandel, E. R. Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 260, 1661–1664 (1993).

  89. 89

    Bailey, C. H., Bartsch, D. & Kandel, E. R. Toward a molecular definition of long-term memory storage. Proc. Natl Acad. Sci. USA 93, 13445–13452 (1996).

  90. 90

    Ma, L., Zablow, L., Kandel, E. R. & Siegelbaum, S. A. Cyclic AMP induces functional presynaptic boutons in hippocampal CA3–CA1 neuronal cultures. Nature Neurosci. 2, 24–30 (1999).

  91. 91

    Makhinson, M., Chotiner, J. K., Watson, J. B. & O'Dell, T. J. Adenylyl cyclase activation modulates activity-dependent changes in synaptic strength and Ca2+/calmodulin-dependent kinase II autophosphorylation. J. Neurosci. 19, 2500–2510 (1999).

  92. 92

    Brown, G. P. et al. Long-term potentiation induced by theta frequency stimulation is regulated by a protein phosphatase-1-operated gate. J. Neurosci. 20, 7880–7887 (2000).

  93. 93

    Zhu, J. J., Esteban, J. A., Hayashi, Y. & Malinow, R. Postnatal synaptic potentiation: delivery of GluR4-containing AMPA receptors by spontaneous activity. Nature Neurosci. 3, 1098–1106 (2000).

  94. 94

    Walaas, S. I. et al. Cell-specific localization of the α-subunit of calcium/calmodulin-dependent protein kinase II in Purkinje cells in rodent cerebellum. Brain Res. 464, 233–242 (1988).

  95. 95

    Burgin, K. E. et al. In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain. J. Neurosci. 10, 1788–1798 (1990).

  96. 96

    Mayford, M., Baranes, D., Podsypanina, K. & Kandel, E. R. The 3′-untranslated region of CaMKII α is a cis-acting signal for the localization and translation of mRNA in dendrites. Proc. Natl Acad. Sci. USA 93, 13250–13255 (1996).

  97. 97

    Mori, Y., Imaizumi, K., Katayama, T., Yoneda, T. & Tohyama, M. Two cis-acting elements in the 3′ untranslated region of α-CaMKII regulate its dendritic targeting. Nature Neurosci. 3, 1079–1084 (2000).

  98. 98

    Rook, M. S., Lu, M. & Kosik, K. S. CaMKIIα 3′ untranslated region-directed mRNA translocation in living neurons: visualization by GFP linkage. J. Neurosci. 20, 6385–6393 (2000).

  99. 99

    Steward, O. & Schuman, E. M. Protein synthesis at synaptic sites on dendrites. Annu. Rev. Neurosci. 24, 299–325 (2001).

  100. 100

    Aakalu, G., Smith, W. B., Nguyen, N., Jiang, C. & Schuman, E. M. Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron 30, 489–502 (2001).

  101. 101

    Giovannini, M. G. et al. Mitogen-activated protein kinase regulates early phosphorylation and delayed expression of Ca2+/calmodulin-dependent protein kinase II in long-term potentiation. J. Neurosci. 21, 7053–7062 (2001).

  102. 102

    Kang, H. et al. An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell 106, 771–783 (2001).

  103. 103

    Frey, U. & Morris, R. G. Synaptic tagging and long-term potentiation. Nature 385, 533–536 (1997).

  104. 104

    Davis, H. P. & Squire, L. R. Protein synthesis and memory: a review. Psychol. Bull. 96, 518–559 (1984).

  105. 105

    Wu, G. Y. & Cline, H. T. Stabilization of dendritic arbor structure in vivo by CaMKII. Science 279, 222–226 (1998).This and the following paper provide clear evidence for CaMKII-mediated structural plasticity during circuit development.

  106. 106

    Zou, D. J. & Cline, H. T. Expression of constitutively active CaMKII in target tissue modifies presynaptic axon arbor growth. Neuron 16, 529–539 (1996).

  107. 107

    Rajan, I. & Cline, H. T. Glutamate receptor activity is required for normal development of tectal cell dendrites in vivo. J. Neurosci. 18, 7836–7846 (1998).

  108. 108

    Zou, D. J. & Cline, H. T. Postsynaptic calcium/calmodulin-dependent protein kinase II is required to limit elaboration of presynaptic and postsynaptic neuronal arbors. J. Neurosci. 19, 8909–8918 (1999).

  109. 109

    Witte, S., Stier, H. & Cline, H. T. In vivo observations of timecourse and distribution of morphological dynamics in Xenopus retinotectal axon arbors. J. Neurobiol. 31, 219–234 (1996).

  110. 110

    Glazewski, S., Chen, C. M., Silva, A. & Fox, K. Requirement for α-CaMKII in experience-dependent plasticity of the barrel cortex. Science 272, 421–423 (1996).

  111. 111

    Glazewski, S., Giese, K. P., Silva, A. & Fox, K. The role of α-CaMKII autophosphorylation in neocortical experience-dependent plasticity. Nature Neurosci. 3, 911–918 (2000).

  112. 112

    Frankland, P. W., O'Brien, C., Ohno, M., Kirkwood, A. & Silva, A. J. α-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 411, 309–313 (2001).

  113. 113

    Hanover, J. L., Taha, A., Silva, A. & Stryker, M. P. Autophosphorylation of CaMKII is necessary for rapid ocular dominance plasticity in primary visual cortex of mouse. Soc. Neurosci. Abstr. 27, 903.6 (2001).

  114. 114

    Silva, A. J. et al. α-Calcium/calmodulin kinase II mutant mice: deficient long-term potentiation and impaired spatial learning. Cold Spring Harb. Symp. Quant. Biol. 57, 527–539 (1992).

  115. 115

    Silva, A. J., Paylor, R., Wehner, J. M. & Tonegawa, S. Impaired spatial learning in α-calcium-calmodulin kinase II mutant mice. Science 257, 206–211 (1992).This groundbreaking paper established the field of mouse behavioural genetics and, together with work in flies, showed a role for CaMKII in complex animal behaviour.

  116. 116

    Cho, Y. H., Giese, K. P., Tanila, H., Silva, A. J. & Eichenbaum, H. Abnormal hippocampal spatial representations in αCaMKIIT286A and CREBαΔ-mice. Science 279, 867–869 (1998).

  117. 117

    Fong, Y. L., Taylor, W. L., Means, A. R. & Soderling, T. R. Studies of the regulatory mechanism of Ca2+/calmodulin-dependent protein kinase II. Mutation of threonine 286 to alanine and aspartate. J. Biol. Chem. 264, 16759–16763 (1989).

  118. 118

    Waldmann, R., Hanson, P. I. & Schulman, H. Multifunctional Ca2+/calmodulin-dependent protein kinase made Ca2+ independent for functional studies. Biochemistry 29, 1679–1684 (1990).

  119. 119

    Mayford, M., Wang, J., Kandel, E. R. & O'Dell, T. J. CaMKII regulates the frequency–response function of hippocampal synapses for the production of both LTD and LTP. Cell 81, 891–904 (1995).A study on the effects of expressing a Ca2+-independent form of CaMKII, which shows changes in the response properties of the synapse that are inconsistent with the literature on CaMKII and are probably confounded by developmental effects of the mutant enzyme.

  120. 120

    Bach, M. E., Hawkins, R. D., Osman, M., Kandel, E. R. & Mayford, M. Impairment of spatial but not contextual memory in CaMKII mutant mice with a selective loss of hippocampal LTP in the range of the theta frequency. Cell 81, 905–915 (1995).

  121. 121

    Wiedenmayer, C. P., Myers, M. M., Mayford, M. & Barr, G. A. Olfactory based spatial learning in neonatal mice and its dependence on CaMKII. Neuroreport 11, 1051–1055 (2000).

  122. 122

    Rotenberg, A., Mayford, M., Hawkins, R. D., Kandel, E. R. & Muller, R. U. Mice expressing activated CaMKII lack low frequency LTP and do not form stable place cells in the CA1 region of the hippocampus. Cell 87, 1351–1361 (1996).

  123. 123

    Mayford, M. et al. Control of memory formation through regulated expression of a CaMKII transgene. Science 274, 1678–1683 (1996).The first attempt to regulate the expression of CaMKII shows that CaMKII activity is required for both learning and recall.

  124. 124

    Koh, Y. H., Popova, E., Thomas, U., Griffith, L. C. & Budnik, V. Regulation of DLG localization at synapses by CaMKII-dependent phosphorylation. Cell 98, 353–363 (1999).

  125. 125

    Griffith, L. C. et al. Inhibition of calcium/calmodulin-dependent protein kinase in Drosophila disrupts behavioral plasticity. Neuron 10, 501–509 (1993).

  126. 126

    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).

Download references


We thank G. Fain, N. Otmakhov and R. Malinow for comments on this review. The authors' work is supported by the National Institutes of Health.

Author information


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

    • John Lisman
  2. Department of Neurobiology, Stanford University School of Medicine, Stanford, 94305, California, USA

    • Howard Schulman
  3. SurroMed Inc., Mountain View, 94043, California, USA

    • Howard Schulman
  4. Cold Spring Harbor Laboratory, Cold Spring Harbor, 11724, New York, USA

    • Hollis Cline


  1. Search for John Lisman in:

  2. Search for Howard Schulman in:

  3. Search for Hollis Cline in:

Corresponding author

Correspondence to John Lisman.

Supplementary information

Related links



An electron-dense thickening underneath the postsynaptic membrane at excitatory synapses that contains receptors, structural proteins linked to the actin cytoskeleton and signalling elements, such as kinases and phosphatases.


During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message. Alternative splicing gives rise to different messages from the same DNA molecule.


“When the axon of cell A excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A's efficiency as one of the cells firing B is increased.”


A train of stimuli in which afferent axons are briefly activated at high frequency. In LTP experiments, a 1-s train of pulses delivered at a frequency of 100 Hz is commonly used to potentiate transmission.


If a cell is artificially depolarized while low-frequency stimulation is delivered, synaptic transmission will be potentiated because the depolarization relieves the Mg2+-dependent block of NMDA receptors.


A mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.


This type of analysis was developed to account for the properties of transmitter release at the neuromuscular junction. It aims to describe release as a function of three basic parameters: the number of release sites (n), the probability of release at each site (p), and the postsynaptic response elicited by a single transmitter vesicle (q). The amplitude of a synaptic event can be described by the product npq. Although quantal analysis provides a valid account of release at the neuromuscular junction, some of its underlying assumptions might not be valid at central synapses.


The synaptic response elicited by a single vesicle of transmitter as determined by postsynaptic factors such as the number and affinity of receptors.


The probability that a presynaptic action potential will fail to produce a postsynaptic response.


A synapse that contains NMDA receptors but no AMPA receptors and is therefore functionally silent during low-frequency, basal synaptic transmission.


A molecule that is involved in the delivery of AMPA-type glutamate receptors to the cell surface. Mice with mutations in this protein — the so-called stargazer mice — arose spontaneously and were detected by their distinctive head-tossing motion and unsteady gait.


A reversal of LTP by low-frequency synaptic stimulation. Depotentiation shares some characteristics with long-term depression; both are induced by low-frequency stimulation, and both require NMDA receptor and protein phosphatase activity. However, it is unclear whether they represent the same phenomenon or are fundamentally different.


A regulatory genetic element that is located in the same DNA molecule as the gene that is being regulated.


Cylindrical columns of neurons that are seen in the rodent somatosensory neocortex. Each barrel receives sensory input from a principal whisker follicle, and the topographical organization of the barrels corresponds precisely to the arrangement of whisker follicles on the face.


The insertion of a mutant gene at the exact site of the genome at which the corresponding wild-type gene is located. This approach is used to ensure that the mutant gene is regulated in the same way as the endogenous locus.


Hippocampal principal cells that fire selectively when an animal is in a particular location in its environment, presumably encoding a spatial map of its surroundings.


A learning task in which an animal is placed in a pool filled with opaque water and has to learn to escape to a hidden platform that is placed at a constant position. The animal must learn to use distal cues, and the spatial relationship between them and the platform. Learning in this task involves the hippocampus.


A system that allows the temporal control of gene expression in eukaryotic systems through the administration of tetracycline. It is based on two key elements: the tetracycline-dependent transactivator protein (tTA) and the target gene under the control of a tTA-responsive element. When these elements are transfected into eukaryotic cells, the tTA binds to the tTA-responsive element to initiate transcription. Tetracycline can then be administered to stop expression of the target gene.

About this article

Publication history

Issue Date


Further reading