Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Bidirectional NMDA receptor plasticity controls CA3 output and heterosynaptic metaplasticity

Nature Neuroscience volume 16, pages 1049–1059 (2013)Cite this article

Subjects

Abstract

NMDA receptors (NMDARs) are classically known as coincidence detectors for the induction of long-term synaptic plasticity and have been implicated in hippocampal CA3 cell–dependent spatial memory functions that likely rely on dynamic cellular ensemble encoding of space. The unique functional properties of both NMDARs and mossy fiber projections to CA3 pyramidal cells place mossy fiber NMDARs in a prime position to influence CA3 ensemble dynamics. By mimicking presynaptic and postsynaptic activity patterns observed in vivo, we found a burst timing–dependent pattern of activity that triggered bidirectional long-term NMDAR plasticity at mossy fiber–CA3 synapses in rat hippocampal slices. This form of plasticity imparts bimodal control of mossy fiber–driven CA3 burst firing and spike temporal fidelity. Moreover, we found that mossy fiber NMDARs mediate heterosynaptic metaplasticity between mossy fiber and associational-commissural synapses. Thus, bidirectional NMDAR plasticity at mossy fiber–CA3 synapses could substantially contribute to the formation, storage and recall of CA3 cell assembly patterns.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Bidirectional burst timing–dependent NMDAR plasticity.
Figure 2: tLTPN and tLTDN exhibit differential sensitivity to group I mGluR antagonism.
Figure 3: Immunoelectron microscopy of mGluR1b and mGluR5 at thorny excrescences.
Figure 4: Mechanistic properties of tLTPN and tLTDN.
Figure 5: Plasticity of mossy fiber–driven burst-firing output endowed by tLTPN and tLTDN.
Figure 6: Bidirectional modulation of CA3 spike temporal fidelity.
Figure 7: Heterosynaptic plasticity mediated by mossy fiber (MF) NMDARs.
Figure 8: Heterosynaptic metaplasticity mediated by NMDAR LTP.

Similar content being viewed by others

References

  1. Daw, N.W., Stein, P.S. & Fox, K. The role of NMDA receptors in information processing. Annu. Rev. Neurosci. 16, 207–222 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Hunt, D.L. & Castillo, P.E. Synaptic plasticity of NMDA receptors: mechanisms and functional implications. Curr. Opin. Neurobiol. 22, 496–508 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Traynelis, S.F. et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62, 405–496 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schiller, J. & Schiller, Y. NMDA receptor-mediated dendritic spikes and coincident signal amplification. Curr. Opin. Neurobiol. 11, 343–348 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Herron, C.E., Lester, R.A., Coan, E.J. & Collingridge, G.L. Frequency-dependent involvement of NMDA receptors in the hippocampus: a novel synaptic mechanism. Nature 322, 265–268 (1986).

    Article  CAS  PubMed  Google Scholar 

  6. Kwon, H.B. & Castillo, P.E. Long-term potentiation selectively expressed by NMDA receptors at hippocampal mossy fiber synapses. Neuron 57, 108–120 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rebola, N., Lujan, R., Cunha, R.A. & Mulle, C. Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses. Neuron 57, 121–134 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Nicoll, R.A. & Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat. Rev. Neurosci. 6, 863–876 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Jonas, P., Major, G. & Sakmann, B. Quantal components of unitary EPSCs at the mossy fibre synapse on CA3 pyramidal cells of rat hippocampus. J. Physiol. (Lond.) 472, 615–663 (1993).

    Article  CAS  Google Scholar 

  10. Rebola, N., Carta, M., Lanore, F., Blanchet, C. & Mulle, C. NMDA receptor-dependent metaplasticity at hippocampal mossy fiber synapses. Nat. Neurosci. 14, 691–693 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Astori, S., Pawlak, V. & Kohr, G. Spike-timing-dependent plasticity in hippocampal CA3 neurons. J. Physiol. (Lond.) 588, 4475–4488 (2010).

    Article  CAS  Google Scholar 

  12. Henze, D.A., Wittner, L. & Buzsaki, G. Single granule cells reliably discharge targets in the hippocampal CA3 network in vivo. Nat. Neurosci. 5, 790–795 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Marr, D. Simple memory: a theory for archicortex. Phil. Trans. R. Soc. Lond. B 262, 23–81 (1971).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Caporale, N. & Dan, Y. Spike timing-dependent plasticity: a Hebbian learning rule. Annu. Rev. Neurosci. 31, 25–46 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Lujan, R., Nusser, Z., Roberts, J.D., Shigemoto, R. & Somogyi, P. Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur. J. Neurosci. 8, 1488–1500 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Morishita, W., Marie, H. & Malenka, R.C. Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses. Nat. Neurosci. 8, 1043–1050 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Peng, Y. et al. Distinct trafficking and expression mechanisms underlie LTP and LTD of NMDA receptor-mediated synaptic responses. Hippocampus 20, 646–658 (2010).

    CAS  PubMed  Google Scholar 

  19. Ireland, D.R. & Abraham, W.C. Mechanisms of group I mGluR-dependent long-term depression of NMDA receptor-mediated transmission at Schaffer collateral-CA1 synapses. J. Neurophysiol. 101, 1375–1385 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Abraham, W.C. Metaplasticity: tuning synapses and networks for plasticity. Nat. Rev. Neurosci. 9, 387–399 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Kobayashi, K. & Poo, M.M. Spike train timing-dependent associative modification of hippocampal CA3 recurrent synapses by mossy fibers. Neuron 41, 445–454 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Kapur, A., Yeckel, M. & Johnston, D. Hippocampal mossy fiber activity evokes Ca2+ release in CA3 pyramidal neurons via a metabotropic glutamate receptor pathway. Neuroscience 107, 59–69 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Ross, W.N. Understanding calcium waves and sparks in central neurons. Nat. Rev. Neurosci. 13, 157–168 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nakashiba, T., Buhl, D.L., McHugh, T.J. & Tonegawa, S. Hippocampal CA3 output is crucial for ripple-associated reactivation and consolidation of memory. Neuron 62, 781–787 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nakazawa, K. et al. Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science 297, 211–218 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakazawa, K. et al. Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 38, 305–315 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Leutgeb, S., Leutgeb, J.K., Moser, M.B. & Moser, E.I. Place cells, spatial maps and the population code for memory. Curr. Opin. Neurobiol. 15, 738–746 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Torborg, C.L., Nakashiba, T., Tonegawa, S. & McBain, C.J. Control of CA3 output by feedforward inhibition despite developmental changes in the excitation-inhibition balance. J. Neurosci. 30, 15628–15637 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mori, M., Abegg, M.H., Gahwiler, B.H. & Gerber, U. A frequency-dependent switch from inhibition to excitation in a hippocampal unitary circuit. Nature 431, 453–456 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Kumar, A., Rotter, S. & Aertsen, A. Spiking activity propagation in neuronal networks: reconciling different perspectives on neural coding. Nat. Rev. Neurosci. 11, 615–627 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Lisman, J.E. Bursts as a unit of neural information: making unreliable synapses reliable. Trends Neurosci. 20, 38–43 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Harnett, M.T., Bernier, B.E., Ahn, K.C. & Morikawa, H. Burst-timing–dependent plasticity of NMDA receptor-mediated transmission in midbrain dopamine neurons. Neuron 62, 826–838 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sjostrom, P.J. & Nelson, S.B. Spike timing, calcium signals and synaptic plasticity. Curr. Opin. Neurobiol. 12, 305–314 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. 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  PubMed  PubMed Central  Google Scholar 

  35. Valenti, O., Conn, P.J. & Marino, M.J. Distinct physiological roles of the Gq-coupled metabotropic glutamate receptors Co-expressed in the same neuronal populations. J. Cell. Physiol. 191, 125–137 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Topolnik, L., Azzi, M., Morin, F., Kougioumoutzakis, A. & Lacaille, J.C. mGluR1/5 subtype-specific calcium signalling and induction of long-term potentiation in rat hippocampal oriens/alveus interneurones. J. Physiol. (Lond.) 575, 115–131 (2006).

    Article  CAS  Google Scholar 

  37. Gerber, U., Gee, C.E. & Benquet, P. Metabotropic glutamate receptors: intracellular signaling pathways. Curr. Opin. Pharmacol. 7, 56–61 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Frausto, S.F., Ito, K., Marszalec, W. & Swanson, G.T. A novel form of low-frequency hippocampal mossy fiber plasticity induced by bimodal mGlu1 receptor signaling. J. Neurosci. 31, 16897–16906 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang, H.X., Gerkin, R.C., Nauen, D.W. & Bi, G.Q. Coactivation and timing-dependent integration of synaptic potentiation and depression. Nat. Neurosci. 8, 187–193 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Buzsaki, G. Neural syntax: cell assemblies, synapsembles, and readers. Neuron 68, 362–385 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bains, J.S., Longacher, J.M. & Staley, K.J. Reciprocal interactions between CA3 network activity and strength of recurrent collateral synapses. Nat. Neurosci. 2, 720–726 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Lawrence, J.J. & McBain, C.J. Interneuron diversity series: containing the detonation–feedforward inhibition in the CA3 hippocampus. Trends Neurosci. 26, 631–640 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Pouille, F. & Scanziani, M. Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition. Science 293, 1159–1163 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Debanne, D., Gahwiler, B.H. & Thompson, S.M. Long-term synaptic plasticity between pairs of individual CA3 pyramidal cells in rat hippocampal slice cultures. J. Physiol. (Lond.) 507, 237–247 (1998).

    Article  CAS  Google Scholar 

  45. Song, S., Miller, K.D. & Abbott, L.F. Competitive Hebbian learning through spike-timing-dependent synaptic plasticity. Nat. Neurosci. 3, 919–926 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Tsukamoto, M. et al. Mossy fibre synaptic NMDA receptors trigger non-Hebbian long-term potentiation at entorhino-CA3 synapses in the rat. J. Physiol. (Lond.) 546, 665–675 (2003).

    Article  CAS  Google Scholar 

  47. Major, G., Polsky, A., Denk, W., Schiller, J. & Tank, D.W. Spatiotemporally graded NMDA spike/plateau potentials in basal dendrites of neocortical pyramidal neurons. J. Neurophysiol. 99, 2584–2601 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Branco, T. & Hausser, M. Synaptic integration gradients in single cortical pyramidal cell dendrites. Neuron 69, 885–892 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nishiyama, M., Hong, K., Mikoshiba, K., Poo, M.M. & Kato, K. Calcium stores regulate the polarity and input specificity of synaptic modification. Nature 408, 584–588 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Hulme, S.R., Jones, O.D., Ireland, D.R. & Abraham, W.C. Calcium-Dependent But Action Potential-Independent BCM-Like Metaplasticity in the Hippocampus. J. Neurosci. 32, 6785–6794 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mateos, J.M. et al. Immunocytochemical localization of the mGluR1b metabotropic glutamate receptor in the rat hypothalamus. J. Comp. Neurol. 390, 225–233 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Ferraguti, F. et al. Immunohistochemical localization of the mGluR1beta metabotropic glutamate receptor in the adult rodent forebrain: evidence for a differential distribution of mGluR1 splice variants. J. Comp. Neurol. 400, 391–407 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Uchigashima, M. et al. Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum. J. Neurosci. 27, 3663–3676 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tanaka, J. et al. Gq protein alpha subunits Galphaq and Galpha11 are localized at postsynaptic extra-junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal cells. Eur. J. Neurosci. 12, 781–792 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of the Castillo lab (in particular, A. Chávez, T. Younts, P. Haeger and S. Makani) for their constructive discussions on the data and helpful comments on the manuscript. This work was supported by US National Institutes of Health grants to P.E.C. (R01 MH081935 and R01 DA017392). Funding for P.G.'s laboratory is provided by Ministerio de Economía y Competitividad (BFU2012-33334), Basque Country Government (IT764-13) and University of the Basque Country.

Author information

Authors and Affiliations

  1. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA

    David L Hunt & Pablo E Castillo

  2. Department of Neurosciences, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain

    Nagore Puente & Pedro Grandes

Authors
  1. David L Hunt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nagore Puente
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pedro Grandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pablo E Castillo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.L.H. and P.E.C. conceived the experimental design of the study. D.L.H. performed and analyzed all electrophysiological experiments. N.P. and P.G. provided electron microscopy data and analysis. D.L.H. and P.E.C. interpreted the results and wrote the paper. All authors commented on the final version of the manuscript.

Corresponding author

Correspondence to Pablo E Castillo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures and Text

Supplementary Figures 1–11 and Supplementary Tables 1 and 2 (PDF 1335 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hunt, D., Puente, N., Grandes, P. et al. Bidirectional NMDA receptor plasticity controls CA3 output and heterosynaptic metaplasticity. Nat Neurosci 16, 1049–1059 (2013). https://doi.org/10.1038/nn.3461

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3461

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing