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Presynaptic kainate receptors impart an associative property to hippocampal mossy fiber long-term potentiation

Nature Neuroscience volume 6, pages 1058–1063 (2003)Cite this article

Abstract

Hippocampal mossy fiber synapses show an unusual form of long-term potentiation (LTP) that is independent of NMDA receptor activation and is expressed presynaptically. Using receptor antagonists, as well as receptor knockout mice, we found that presynaptic kainate receptors facilitate the induction of mossy fiber long-term potentiation (LTP), although they are not required for this form of LTP. Most importantly, these receptors impart an associativity to mossy fiber LTP such that activity in neighboring mossy fiber synapses, or even associational/commissural synapses, influences the threshold for inducing mossy fiber LTP. Such a mechanism greatly increases the computational power of this form of plasticity.

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Figure 1: KAR blockade increases the threshold for LTP induction.
Figure 2: KAR blockade shifts the threshold for LTP induction.
Figure 3: KARs modulate the threshold for LTP induction as monitored with field potential recordings.
Figure 4: Application of K+ converts a subthreshold tetanus into an effective one.
Figure 5: Application of K+ or strong tetani rescue mossy fiber LTP in the GluR6 knockout mouse.
Figure 6: KARs impart a cooperativity/associativity to mossy fiber LTP.
Figure 7: The cooperativity/associativity of mossy fiber LTP is mediated by KARs.

References

  1. Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).

    Article  CAS  Google Scholar 

  2. Dingledine, R., Borges, K., Bowie, D. & Traynelis, S.F. The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61 (1999).

    CAS  Google Scholar 

  3. Malenka, R.C. & Nicoll, R.A. Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Harris, E.W. & Cotman, C.W. Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl-D-aspartate antagonists. Neurosci. Lett. 70, 132–137 (1986).

    Article  CAS  Google Scholar 

  6. Zalutsky, R.A. & Nicoll, R.A. Comparison of two forms of long-term potentiation in single hippocampal neurons. Science 248, 1619–1624 (1990).

    Article  CAS  Google Scholar 

  7. Chattarji, S., Stanton, P.K. & Sejnowski, T.J. Commissural synapses, but not mossy fiber synapses, in hippocampal field CA3 exhibit associative long-term potentiation and depression. Brain Res. 495, 145–150 (1989).

    Article  CAS  Google Scholar 

  8. Zalutsky, R.A. & Nicoll, R.A. Mossy fiber long-term potentiation shows specificity but no apparent cooperativity. Neurosci. Lett. 138, 193–197 (1992).

    Article  CAS  Google Scholar 

  9. Langdon, R.B., Johnson, J.W. & Barrionuevo, G. Posttetanic potentiation and presynaptically induced long-term potentiation at the mossy fiber synapse in rat hippocampus. J. Neurobiol. 26, 370–385 (1995).

    Article  CAS  Google Scholar 

  10. Ito, I. & Sugiyama, H. Roles of glutamate receptors in long-term potentiation at hippocampal mossy fiber synapses. Neuroreport 2, 333–336 (1991).

    Article  CAS  Google Scholar 

  11. Tong, G., Malenka, R.C. & Nicoll, R.A. Long-term potentiation in cultures of single hippocampal granule cells: a presynaptic form of plasticity. Neuron 16, 1147–1157 (1996).

    Article  CAS  Google Scholar 

  12. Weisskopf, M.G. & Nicoll, R.A. Presynaptic changes during mossy fibre LTP revealed by NMDA receptor-mediated synaptic responses. Nature 376, 256–259 (1995).

    Article  CAS  Google Scholar 

  13. Castillo, P.E., Weisskopf, M.G. & Nicoll, R.A. The role of Ca2+ channels in hippocampal mossy fiber synaptic transmission and long-term potentiation. Neuron 12, 261–269 (1994).

    Article  CAS  Google Scholar 

  14. Yeckel, M.F., Kapur, A. & Johnston, D. Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism. Nat. Neurosci. 2, 625–633 (1999).

    Article  CAS  Google Scholar 

  15. Bortolotto, Z.A. et al. Kainate receptors are involved in synaptic plasticity. Nature 402, 297–301 (1999).

    Article  CAS  Google Scholar 

  16. Mellor, J. & Nicoll, R.A. Hippocampal mossy fiber LTP is independent of postsynaptic calcium. Nat. Neurosci. 4, 125–126 (2001).

    Article  CAS  Google Scholar 

  17. 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 

  18. Lauri, S.E. et al. A critical role of a facilitatory presynaptic kainate receptor in mossy fiber LTP. Neuron 32, 697–709 (2001).

    Article  CAS  Google Scholar 

  19. Contractor, A., Swanson, G. & Heinemann, S.F. Kainate receptors are involved in short- and long-term plasticity at mossy fiber synapses in the hippocampus. Neuron 29, 209–216 (2001).

    Article  CAS  Google Scholar 

  20. Nicoll, R.A., Mellor, J., Frerking, M. & Schmitz, D. Kainate receptors and synaptic plasticity. Nature 406, 957 (2000).

    Article  CAS  Google Scholar 

  21. Bortolotto, Z.A., Clarke, V.R.J., Delany, C.M., Vignes, M. & Collingridge, G.L. Kainate receptors and synaptic plasticity. Nature 406, 957 (2000).

    Article  Google Scholar 

  22. Kamiya, H. & Ozawa, S. Kainate receptor-mediated presynaptic inhibition at the mouse hippocampal mossy fibre synapse. J. Physiol. 523, 653–665 (2000).

    Article  CAS  Google Scholar 

  23. Schmitz, D., Frerking, M. & Nicoll, R.A. Synaptic activation of presynaptic kainate receptors on hippocampal mossy fiber synapses. Neuron 27, 327–338 (2000).

    Article  CAS  Google Scholar 

  24. Contractor, A., Swanson, G.T., Sailer, A., O'Gorman, S. & Heinemann, S.F. Identification of the kainate receptor subunits underlying modulation of excitatory synaptic transmission in the CA3 region of the hippocampus. J. Neurosci. 20, 8269–8278 (2000).

    Article  CAS  Google Scholar 

  25. Schmitz, D., Mellor, J., Frerking, M. & Nicoll, R.A. Presynaptic kainate receptors at hippocampal mossy fiber synapses. Proc. Natl. Acad. Sci. USA 98, 11003–11008 (2001).

    Article  CAS  Google Scholar 

  26. Schmitz, D., Mellor, J. & Nicoll, R.A. Presynaptic kainate receptor mediation of frequency facilitation at hippocampal mossy fiber synapses. Science 291, 1972–1976 (2001).

    Article  CAS  Google Scholar 

  27. Kamiya, H., Shinozaki, H. & Yamamoto, C. Activation of metabotropic glutamate receptor type 2/3 suppresses transmission at rat hippocampal mossy fibre synapses. J. Physiol. 493, 447–455 (1996).

    Article  CAS  Google Scholar 

  28. Bureau, I., Bischoff, S., Heinemann, S.F. & Mulle, C. Kainate receptor-mediated responses in the CA1 field of wild-type and GluR6-deficient mice. J. Neurosci. 19, 653–663 (1999).

    Article  CAS  Google Scholar 

  29. Contractor, A. et al. Loss of kainate receptor-mediated heterosynaptic facilitation of mossy-fiber synapses in KA2−/− mice. J. Neurosci. 23, 422–429 (2003).

    Article  CAS  Google Scholar 

  30. Monaghan, D.T. & Cotman, C.W. The distribution of [3H]kainic acid binding sites in rat CNS as determined by autoradiography. Brain Res. 252, 91–100 (1982).

    Article  CAS  Google Scholar 

  31. Represa, A., Tremblay, E. & Ben-Ari, Y. Kainate binding sites in the hippocampal mossy fibers: localization and plasticity. Neuroscience 20, 739–748 (1987).

    Article  CAS  Google Scholar 

  32. Ji, Z. & Staubli, U. Presynaptic kainate receptors play different physiological roles in mossy fiber and associational-commissural synapses in CA3 of hippocampus from adult rats. Neurosci. Lett. 331, 71–74 (2002).

    Article  CAS  Google Scholar 

  33. Kamiya, H., Ozawa, S. & Manabe, T. Kainate receptor-dependent short-term plac=sticity of presynaptic Ca2+ influx at the hippocampal mossy fiber synapses. J. Neurosci. 22, 9237–9243 (2002).

    Article  CAS  Google Scholar 

  34. Geiger, J.R.P. & Jonas, P. Dynamic control of presynaptic Ca2+ inflow by fast-inactivating K+ channels in hippocampal mossy fiber boutons. Neuron 28, 927–929 (2000).

    Article  CAS  Google Scholar 

  35. Henze, D.A., Urban, N.N. & Barrionuevo, G. The multifarious hippocampal mossy fiber pathway: a review. Neuroscience 98, 407–427 (2000).

    Article  CAS  Google Scholar 

  36. Contractor, A. et al. Trans-synaptic Eph receptor-ephrin signaling in hippocampal mossy fiber LTP. Science 296, 1864–1869 (2002).

    Article  CAS  Google Scholar 

  37. Jung, M.W. & McNaughton, B.L. Spatial selectivity of unit activity in the hippocampal granular layer. Hippocampus 3, 165–182 (1993).

    Article  CAS  Google Scholar 

  38. Wiebe, S.P. & Staubli, U.V. Dynamic filtering of recognition memory codes in the hippocampus. J. Neurosci. 19, 10562–10574 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Frerking for his helpful discussions in this study. D.S. is supported by grants from the Deutsche Forschungsgemeinschaft (Emmy-Noether-Programm, SFB618) and J.M. by a Wellcome Trust Travelling Fellowship. R.A.N. is a member of the Keck Center for Integrative Neuroscience and the Silvio Conte Center for Neuroscience Research and is supported by grants from the US National Institutes of Health and the Bristol-Myers Squibb Co. We thank S. Heinemann for the GluR5 and GluR6 knockout mice and S. Karimzadegan for technical assistance.

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  1. Dietmar Schmitz and Jack Mellor: These authors contributed equally to this work.

Authors and Affiliations

  1. Neuroscience Research Center, Charité, Humboldt-University Berlin, Schumannstr. 20/21, Berlin, 10117, Germany

    Dietmar Schmitz & Joerg Breustedt

  2. Department of Anatomy, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK

    Jack Mellor

  3. Department of Cellular and Molecular Pharmacology and Department of Physiology, University of California, Box 2140 Mission Bay Campus, 600 16 Street, San Francisco, 94143, California, USA

    Roger A Nicoll

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Correspondence to Roger A Nicoll.

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Schmitz, D., Mellor, J., Breustedt, J. et al. Presynaptic kainate receptors impart an associative property to hippocampal mossy fiber long-term potentiation. Nat Neurosci 6, 1058–1063 (2003). https://doi.org/10.1038/nn1116

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