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CaMKII regulates the density of central glutamatergic synapses in vivo

Nature volume 402, pages 195–199 (1999)Cite this article

Abstract

Synaptic connections undergo a dynamic process of stabilization or elimination during development, and this process is thought to be critical in memory and learning and in establishing the specificity of synaptic connections1. The type II calcium- and calmodulin-dependent protein kinase (CaMKII) has been proposed to be pivotal in regulating synaptic strength2,3,4 and in maturation of synapses during development5. Here we describe how CaMKII regulates the formation of central glutamatergic synapses in Caenorhabditis elegans. During larval development, the density of ventral nerve cord synapses containing the GLR-1 glutamate receptor is held constant despite marked changes in neurite length. The coupling of synapse number to neurite length requires both CaMKII and voltage-gated calcium channels. CaMKII regulates GLR-1 by at least two distinct mechanisms: regulating transport of GLR-1 from cell bodies to neurites; and regulating the addition or maintenance of GLR-1 to postsynaptic elements.

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Figure 1: Formation of GLR-1::GFP clusters.
Figure 2: Mutants lacking the unc-43 CaMKII accumulate GLR-1::GFP receptors in neuron cell bodies.
Figure 3: GFP::UNC-43 is localized to clusters in the ventral cord processes.
Figure 4: A model for CaMKII regulation of synaptic density.

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References

  1. Hebb,D. The Organization of Behavior (Wiley, New York, 1949).

    Google Scholar 

  2. Stevens,C., Tonegawa,S. & Wang,Y. The role of calcium-calmodulin kinase II in three forms of synaptic plasticity. Curr. Biol. 4, 687–693 (1994).

    Article  CAS  Google Scholar 

  3. Mayford,M., Wang,J., Kandel,E. & O'Dell,T. CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP. Cell 81, 891–904 (1995).

    Article  CAS  Google Scholar 

  4. Lisman,J., Malenka,R. C., Nicoll,R. A. & Malinow,R. Learning mechanisms: the case for CaM-KII. Science 276, 2001–2002 (1997).

    Article  CAS  Google Scholar 

  5. Wu,G., Malinow,R. & Cline,H. Maturation of a central glutamatergic synapse. Science 274, 972–976 (1996).

    Article  ADS  CAS  Google Scholar 

  6. Hart,A., Sims,S. & Kaplan,J. A synaptic code for sensory modalities revealed by analysis of the C. elegans GLR-1 glutamate receptor. Nature 378, 82–85 (1995).

    Article  ADS  CAS  Google Scholar 

  7. Maricq,A. V., Peckol,E., Driscoll,M. & Bargmann,C. glr-1, a C. elegans glutamate receptor that mediates mechanosensory signalling. Nature 278, 78–81 (1995).

    Article  ADS  Google Scholar 

  8. Rongo,C., Whitfield,C. W., Rodal,A., Kim,S. K. & Kaplan,J. M. LIN-10 is a shared component of the polarized protein localization pathways in neurons and epithelia. Cell 94, 751–759 (1998).

    Article  CAS  Google Scholar 

  9. White,J. G., Southgate,E., Thomson,J. N. & Brenner,S. The structure of the nervous system of Caenorhabditis elegans. Phil. Trans. R. Soc. Lond. 314, 1–340 (1986).

    Article  CAS  Google Scholar 

  10. Sulston,J. E. & Horvitz,H. R. Abnormal cell lineages in mutants of the nematode Caenorhabditis elegans. Dev. Biol. 82, 41–55 (1981).

    Article  CAS  Google Scholar 

  11. Turrigiano,G. G. Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same. Trends Neurosci. 22, 221–227 (1999).

    Article  CAS  Google Scholar 

  12. Riddle,D., Blumenthal,T., Meyer,B. & Priess,J. (eds) C. elegans II (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1997).

  13. Rao,A. & Craig,A. M. Activity regulates the synaptic localization of the NMDA receptor in hippocampal neurons. Neuron 19, 801–812 (1997).

    Article  CAS  Google Scholar 

  14. O'Brien,R. J. et al. Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron 21, 1067–1078 (1998).

    Article  CAS  Google Scholar 

  15. Reiner,D. J., Newton,E. M., Tian,H. & Thomas,J. H. Diverse behavioural defects caused by mutations in Caenorhabditis elegans unc-43 CaM Kinase II. Nature 402, 199–203 (1999).

    Article  ADS  CAS  Google Scholar 

  16. 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).

    CAS  PubMed  Google Scholar 

  17. Schafer,W. & Kenyon,C. A calcium-channel homologue required for adaptation to dopamine and serotonin in C. elegans. Nature 375, 73–78 (1995).

    Article  ADS  CAS  Google Scholar 

  18. Lee,R., Lobel,L., Hengartner,M., Horvitz,H. & Avery,L. Mutations in the alpha1 subunit of an L-type voltage-activated Ca2+ channel cause myotonia in Caenorhabditis elegans. EMBO J. 16, 6066–6076 (1997).

    Article  CAS  Google Scholar 

  19. Wu,G. Y. & Cline,H. T. Stabilization of dendritic arbor structure in vivo by CaMKII. Science 279, 222–226 (1998).

    Article  ADS  CAS  Google Scholar 

  20. Nonet,M., Saifee,O., Zhao,H., Rand,J. & Wei,L. Synaptic transmission deficits in Caenorhabditis elegans synaptobrevin mutants. J. Neurosci. 18, 70–80 (1998).

    Article  CAS  Google Scholar 

  21. Carroll,R. C., Lissin,D. V., von Zastrow,M., Nicoll,R. A. & Malenka,R. C. Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures. Nature Neurosci. 2, 454–460 (1999).

    Article  CAS  Google Scholar 

  22. Liao,D., Zhang,X., O'Brien,R., Ehlers,M. D. & Huganir,R. L. Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons. Nature Neurosci. 2, 37–43 (1999).

    Article  CAS  Google Scholar 

  23. 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  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  ADS  CAS  Google Scholar 

  25. Barria,A., Derkach,V. & Soderling,T. Identification of the Ca2+/calmodulin-dependent protein kinase II regulatory phosphorylation site in the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate-type glutamate receptor. J. Biol. Chem. 272, 32727–32730 (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-methylisoxazole-4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II. J. Biol. Chem. 272, 32528–32533 (1997).

    Article  CAS  Google Scholar 

  27. Kim,J. H. & Huganir,R. L. Organization and regulation of proteins at synapses. Curr. Opin. Cell Biol. 11, 248–254 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Reiner and J. Thomas for sharing unpublished data. In addition, we thank M. Kennedy, H. Schulman, A. Fire, R. Barstead, A. Hart, J. Mendel, C. Mello and V. Maricq for providing plasmids and antibodies, and the C. elegans genome sequencing consortium for providing sequence. Some strains were provided by the C. elegans Genetics Center. We thank T. Serafini, E. Isacoff, G. Garriga and members of the Kaplan lab for comments on the manuscript. This work was supported by grants from the NIH and the Pew Charitable Trust (J.K.) and by a fellowship from Jane Coffin Childs (C.R.).

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  1. Department of Molecular and Cell Biology, LSA 361, University of California, Berkeley, 94720-3200, California, USA

    Christopher Rongo & Joshua M. Kaplan

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  1. Christopher Rongo
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  2. Joshua M. Kaplan
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Correspondence to Joshua M. Kaplan.

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Rongo, C., Kaplan, J. CaMKII regulates the density of central glutamatergic synapses in vivo. Nature 402, 195–199 (1999). https://doi.org/10.1038/46065

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