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NMDA receptors amplify calcium influx into dendritic spines during associative pre- and postsynaptic activation

Abstract

Long-term potentiation (LTP) of synaptic strength can be induced by synchronous pre- and post-synaptic activation, and a rise in postsynaptic calcium is essential for induction of LTP. Calcium can enter through both voltage-dependent Ca2+ channels and NMDA-type glutamate receptors, but the relative contributions of these pathways is not known. We have examined this issue in layer V cortical pyramidal neurons, using focal flash photolysis of caged glutamate to mimic synaptic input and two-photon, laser-scanning microscopy to measure calcium levels in dendritic spines. Most of the calcium entry in response to glutamate alone was via voltage-dependent Ca2+ channels, and NMDA receptors accounted for less than 20% of total Ca2+ entry. When glutamate was paired with postsynaptic action potentials, however, the NMDA-receptor-dependent component was selectively amplified. The same is likely to occur during paired physiological pre- and postsynaptic activation, providing a mechanism for the input specificity and Hebbian behavior of LTP.

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Figure 1: Pairing of EPSLP's and action potentials results in supralinear accumulation of Ca2+ in the dendritic spine.
Figure 2: Comparison of Ca2+ transients developing in the spine and adjacent parent dendrite.
Figure 3: The relative contribution of various VDCC subtypes to Ca2+ transients developing in dendritic spines and adjacent parent dendrites.
Figure 4: Amplification of Ca2+ influx into dendritic spines through the NMDA receptor channel during the pairing protocol.

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References

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

    Article  CAS  Google Scholar 

  2. Nicoll, R.A. & Malenka, R.C. Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature 377, 115–118 (1995)

    Article  CAS  Google Scholar 

  3. Kirkwood, A. & Bear M.F. Elementary forms of synaptic plasticity in the visual cortex. Biol. Res. 28, 73– 80 (1995)

    CAS  PubMed  Google Scholar 

  4. Eilers, J., Augustine, G.J. & Konnerth, A. Subthreshold synaptic Ca2+ signalling in fine dendrites and spines of cerebellar Purkinje neurons. Nature 373, 107–108 ( 1995)

    Article  Google Scholar 

  5. Petrozzino, J.J., Pozzo Miller L.D. & Connor, J.A. Micromolar Ca2+ transients in dendritic spines of hippocampal pyramidal neurons in brain slice. Neuron 14, 1223–1231 ( 1995)

    Article  CAS  Google Scholar 

  6. Yuste, R. & Denk, W. Dendritic spines as basic functional units of neuronal integration. Nature 375, 682–684 (1995)

    Article  CAS  Google Scholar 

  7. Denk, W., Sugimori, M. & Llinas, R. Two types of calcium response limited to single spines in cerebellar Purkinje cells. PNAS 92, 8279–8282 (1996)

    Article  Google Scholar 

  8. Johnston, D., Magee J.C., Colbert C.M. & Cristie B.R. Active properties of neuronal dendrites. Annu. Rev. Neurosci. 19, 165–186 (1996)

    Article  CAS  Google Scholar 

  9. Yuste, R. & Tank, D.W. Dendritic integration in mammalian neurons, a century after Cajal. Neuron 16, 701–716 (1996)

    Article  CAS  Google Scholar 

  10. Magee, J.C. & Johnston, D. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275, 209–213 (1997)

    Article  CAS  Google Scholar 

  11. Eilers, J. & Konnerth, A. Dendritic signal integration. Curr. Opin. Neurobiol. 7, 385–90 (1997)

    Article  CAS  Google Scholar 

  12. Regehr, W.G. & Tank, D.W. Postsynaptic NMDA receptor-mediated calcium accumulation in hippocampal CA1 pyramidal cell dendrites. Nature 345, 807–810 ( 1990)

    Article  CAS  Google Scholar 

  13. Miyakawa, H. et al. Synaptically activated increases in Ca2+ concentration in hippocampal CA1 pyramidal cells are primarily due to voltage-gated Ca2+ channels. Neuron 9, 1163– 1173 (1992)

    Article  CAS  Google Scholar 

  14. Schiller, J., Schiller, Y., Stuart, G. & Sakmann, B. Calcium action potentials restricted to distal apical dendrites in rat neocortical pyramidal neurons. J. Physiol. 505, 605– 616 (1997)

    Article  CAS  Google Scholar 

  15. Dunlap, K., Luebke, J.I. & Turner, T.J. Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci. 18, 89– 98 (1995)

    Article  CAS  Google Scholar 

  16. Svoboda, K., Tank, D.W. & Denk. W .Direct measurement of coupling between dendritic spines and shafts. Science 272, 716–719 ( 1996)

    Article  CAS  Google Scholar 

  17. Olivera, B.M. et al. Peptide neurotoxins from fish-hunting cone snails. Science 230, 1338–43 (1985)

    Article  CAS  Google Scholar 

  18. Fox, A.P., Nowycky, M.C. & Tsien, R.W. Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones. J. Physiol. 394 , 149–172 (1987)

    Article  CAS  Google Scholar 

  19. Llinas, R., Sugimori, M., Lin, J.W. & Cherksey, B. Blocking and isolation of a calcium channel from neurons in mammals and cephalopods utilizing a toxin fraction (FTX) from funnel-web spider poison. Proc. Natl. Acad. Sci. USA 86, 1689–1693 (1989)

    Article  CAS  Google Scholar 

  20. Magee, J.C. & Johnston, D. Characterization of single voltage-gated Na+ and Ca2+ channels in apical dendrites of rat CA1 pyramidal neurons. J. Physiol. 487, 67–90 (1995)

    Article  CAS  Google Scholar 

  21. Markram, H., Helm, P.J. & Sakmann, B. Dendritic calcium transients evoked by single back-propagating action potentials in rat neocortical pyramidal neurons. J. Physiol. 485 , 1–20 (1995)

    Article  CAS  Google Scholar 

  22. Schiller, J., Helmchen, F. & Sakmann, B. Spatial profile of dendritic calcium transients evoked by action potentials in rat neocortical pyramidal neurones. J. Physiol. 487, 583–600 (1995)

    Article  CAS  Google Scholar 

  23. Christie, B.R., Eliot, L.S., Ito, K., Miyakawa, H. & Johnston, D. Different Ca2+ channels in soma and dendrites of hippocampal pyramidal neurons mediate spike-induced Ca2+ influx. J. Neurophysiol. 73, 2553– 2557 (1995)

    Article  CAS  Google Scholar 

  24. Mayer, M.L. & Westbrook, G.L. The physiology of excitatory amino acids in the vertebrate central nervous. Prog. Neurobiol. 28, 197–276 ( 1987)

    Article  CAS  Google Scholar 

  25. Mayer, M.L., Vyklicky L.Jr. & Westbrook, G.L. Modulation of excitatory amino acid receptors by group IIB metal cations in cultured mouse hippocampal neurons. J. Physiol. 415, 329–350 ( 1989)

    Article  CAS  Google Scholar 

  26. Spruston, N., Jonas, P., & Sakmann, B. Dendritic glutamate receptor channels in rat hippocampal CA3 and CA1 pyramidal neurons. J. Physiol. 482, 325– 352 (1995)

    Article  CAS  Google Scholar 

  27. Schuman, E.M. Synapse specificity and long term information storage. Neuron 18, 339–342 (1997)

    Article  CAS  Google Scholar 

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

    Google Scholar 

  29. Stuart, G.J., Dodt, H.U. & Sakmann, B. Patch-clamp recordings from the soma and dendrites of neurons in brain slices using infrared video microscopy. Pflug. Archiv. - Europ. J. Physiol . 423, 511–518 ( 1993)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Ryan Bortolon for excellent technical assistance, David Wokosin and John White of the University of Wisconsin Microscopy Laboratory for their generous help and advice, and Frank Prendergast and the Mayo Foundation for their support. This work was funded by the Howard Hughes Medical Institute (DEC) and a grant from the NIH (DEC).

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Correspondence to David E. Clapham.

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Schiller, J., Schiller, Y. & Clapham, D. NMDA receptors amplify calcium influx into dendritic spines during associative pre- and postsynaptic activation. Nat Neurosci 1, 114–118 (1998). https://doi.org/10.1038/363

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