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The role of α-CaMKII autophosphorylation in neocortical experience-dependent plasticity

Nature Neuroscience volume 3, pages 911–918 (2000)Cite this article

Abstract

Calcium/calmodulin kinase type II (CaMKII) is a major postsynaptic density protein. CaMKII is postulated to act as a ‘molecular switch’, which, when triggered by a transient rise in calcium influx, becomes active for prolonged periods because of its ability to autophosphorylate. We studied experience-dependent plasticity in the barrel cortex of mice carrying a point mutation of the α-CaMKII gene (T286A), which abolishes this enzyme's ability to autophosphorylate. Plasticity was prevented in adult and adolescent mice homozygous for the mutation, but was normal in heterozygotes and wild-type littermates. These results provide evidence that the molecular switch hypothesis is valid for neocortical experience-dependent plasticity.

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Figure 1: The spared D1 vibrissa domain expands in adult wild-type mice but not in T286A littermates following deprivation.
Figure 2: Vibrissae dominance histograms shift because of potentiation in wild-type mice but do not shift in T286A homozygotes.
Figure 3: The spared vibrissa domain does not expand for deprived adolescent T286A mutants.
Figure 4: Vibrissae dominance and principal whisker response depression in adolescents (conventions same as in Fig. 2).
Figure 5: Absolute magnitude of response to stimulation of surround receptive field whiskers in α-CaMKII mutants and their wild-type littermates.

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References

  1. 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).

    Article  CAS  Google Scholar 

  2. Malenka, R. C., Kauer, J. A., Zucker, R. S. & Nicoll, R. A. Postsynaptic calcium is sufficient for potentiation of hippocampal synaptic transmission. Science 242, 81– 84 (1988).

    Article  CAS  Google Scholar 

  3. Bhalla, U. S. & Iyengar, R. Emergent properties of networks of biological signaling pathways. Science 283, 381–387 (1999).

    Article  CAS  Google Scholar 

  4. Kennedy, M. B., Bennett, M. K. & Erondu, N. E. Biochemical and immunochemical evidence that the “major postsynaptic density protein” is a subunit of a calmodulin-dependent protein kinase. Proc. Natl. Acad. Sci. USA 80, 7357–7361 (1983).

    Article  CAS  Google Scholar 

  5. Miller, S. G. & Kennedy, M. B. Distinct forebrain and cerebellar isozymes of type II Ca2+/calmodulin-dependent protein kinase associate differently with the postsynaptic density fraction. J. Biol. Chem. 260, 9039–9046 (1985).

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Kirkwood, A., Silva, A. & Bear, M. F. Age-dependent decrease of synaptic plasticity in the neocortex of alphaCaMKII mutant mice. Proc. Natl. Acad. Sci. USA 94, 3380–3383 (1997).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Lisman, J. & Goldring, M. Evaluation of a model of long-term memory based on the properties of the Ca2+/calmodulin-dependent protein kinase. Journal de Physiologie 83, 187–197 (1988).

    Google Scholar 

  11. Lisman, J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc. Natl. Acad. Sci. USA 86, 9574 –9578 (1989).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Ouyang, Y., Rosenstein, A., Gabriel, K., Schuman, E. R. & 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).

    Article  CAS  Google Scholar 

  15. Fox, K. The cortical component of experience-dependent synaptic plasticity in rat barrel cortex. J. Neurosci. 14, 7665– 7679 (1994).

    Article  CAS  Google Scholar 

  16. Wallace, H. & Fox, K. The effect of chessboard deprivation pattern on potentiation and depression of vibrissae responses in rat barrel cortex. Somatosens. Mot. Res. 16, 122– 138 (1999).

    Article  CAS  Google Scholar 

  17. Glazewski, S., McKenna, M., Jacquin, M. & Fox, K. Experience-dependent depression of vibrissae responses in rat barrel cortex. Eur. J. Neurosci. 10, 2107–2116 (1998).

    Article  CAS  Google Scholar 

  18. Glazewski, S., Chen, C.-H., Silva, A. & Fox, K. The requirement for αCAMKII in experience-dependent plasticity of the barrel cortex. Science 272, 421–423 (1996).

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Glazewski, S. et al. Impaired experience-dependent plasticity in barrel cortex of mice lacking the alpha and delta isoforms of CREB. Cereb. Cortex 9, 249–256 (1999).

    Article  CAS  Google Scholar 

  21. Welker, E. et al. Altered sensory processing in the somatosensory cortex of the mouse mutant barrelless. Science 27, 1864–1867 (1996).

    Article  Google Scholar 

  22. Fox, K., Schlaggar, B. L., Glazewski, S. & O'Leary, D. M. M. Glutamate blockade at cortical synapses disrupts development of thalamocortical and columnar organization in somatosensory cortex. Proc. Natl. Acad. Sci. USA 93, 5584–5589 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. 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  Google Scholar 

  26. Mammen, A. L., Kameyama, K., Roche, K. W. & Huganir, R. L. Phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II. J. Biol. Chem. 272, 32528–32533 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Hendry, S. H. & Kennedy, M. B. Immunoreactivity for a calmodulin-dependent protein kinase is selectively increased in macaque striate cortex after monocular deprivation. Proc. Natl. Acad. Sci. USA 83, 1536–1541 (1986).

    Article  CAS  Google Scholar 

  29. Gordon, J. A., Cioffi, D., Silva, A. J. & Stryker, M. P. Deficient plasticity in the primary visual cortex of alpha-calcium/calmodulin-dependent protein kinase II mutant mice. Neuron 17, 491– 499 (1996).

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  31. Benson, D. L., Isackson, P. J., Hendry, S. H. & Jones E. G. Differential gene expression for glutamic acid decarboxylase and type II calcium-calmodulin-dependent protein kinase in basal ganglia, thalamus, and hypothalamus of the monkey . J. Neurosci. 11, 1540– 1564 (1991).

    Article  CAS  Google Scholar 

  32. Benson, D. L., Isackson, P. J., Gall, C. M. & Jones E. G. Contrasting patterns in the localization of glutamic acid decarboxylase and Ca2+/calmodulin protein kinase gene expression in the rat central nervous system. Neuroscience 46, 825– 849 (1992).

    Article  CAS  Google Scholar 

  33. Jones, E. G., Huntley, G. W. & Benson, D. L. Alpha calcium/calmodulin-dependent protein kinase II selectively expressed in a subpopulation of excitatory neurons in monkey sensory-motor cortex: comparison with GAD-67 expression. J. Neurosci. 14, 611–629 (1994).

    Article  CAS  Google Scholar 

  34. Sik, A., Hajos, N., Gulacsi, A., Mody, I. & Freund, T. F. The absence of a major Ca2+ signaling pathway in GABAergic neurons of the hippocampus. Proc. Natl. Acad. Sci. USA 95, 3245–3250 (1998).

    Article  CAS  Google Scholar 

  35. Liu, X. B. & Jones, E. G. Localization of alpha type II calcium calmodulin-dependent protein kinase at glutamatergic but not gamma-aminobutyric acid (GABAergic) synapses in thalamus and cerebral cortex. Proc. Natl. Acad. Sci. USA 93, 7332–7336 (1996).

    Article  CAS  Google Scholar 

  36. Fox, K. A critical period for experience dependent plasticity in somatosensory cortex . J. Neurosci. 12, 1826– 1838 (1992).

    Article  CAS  Google Scholar 

  37. 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).

    Article  CAS  Google Scholar 

  38. Li, X., Glazewski, S., Lin, X., Elde, R. & Fox, K. The effect of vibrissae deprivation on follicle innervation, neuropeptide synthesis in the trigeminal ganglion and S1 barrel field cortical plasticity . J. Comp. Neurol. 357, 465– 481 (1995).

    Article  CAS  Google Scholar 

  39. Wong-Riley, M. Changes in visual system of monocularly sutured or enucleated cats demonstrable with cytochrome oxidase histochemistry. Brain Res. 171, 11–28 (1979).

    Article  CAS  Google Scholar 

  40. Glazewski, S. & Fox, K. The time-course of experience-dependent synaptic potentiation and depression in barrel cortex of adolescent rats. J. Neurophysiol. 75, 1714–1729 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Paul Chapman and Frank Sengpiel for critical reading of the text and Mervyn McKenna for histology. This work was supported by grants from NIH NS27759 and MRC(UK) to K.F. K.P.G. was supported by the German Research Council (DFG).

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Authors and Affiliations

  1. Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3US, UK

    S. Glazewski & K. Fox

  2. Department of Anatomy and Developmental Biology, University College London, London, WC1E 6BT, UK

    K. P. Giese

  3. Departments of Neurobiology, Psychology and Psychiatry University of California, Los Angeles, 695 Young Drive South, Room 2357, Los Angeles, 90095, California, USA

    A. Silva

Authors
  1. S. Glazewski
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  2. K. P. Giese
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  3. A. Silva
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  4. K. Fox
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Corresponding author

Correspondence to K. Fox.

Supplementary information

Figure. Plasticity in adolescent T286A mutants

The effect of 18 days of deprivation on responses to D1 and principal vibrissae stimulation in adolescent T-286 homozygotes. Each point represents data from a single cell recorded in layers 2/3. The cell's response to the spared D1 vibrissa is plotted against its response to the deprived principal vibrissa. Equal responses from both vibrissae result in a point on the dashed line (45 degree line). Note that, in spite of deprivation, most cells are dominated by the deprived principal vibrissa. Additionally, domination of the remaining cells by the D1 vibrissa is due to depression of the deprived principal vibrissa response rather than potentiation of the D1 response. In contrast, in wild-type animals, plasticity is expressed mainly by potentiation of the D1 input (see Fig. 4 in ref. 40 for comparison). (GIF 168 kb)

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Glazewski, S., Giese, K., Silva, A. et al. The role of α-CaMKII autophosphorylation in neocortical experience-dependent plasticity. Nat Neurosci 3, 911–918 (2000). https://doi.org/10.1038/78820

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