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Bidirectional NMDA receptor plasticity controls CA3 output and heterosynaptic metaplasticity

Nature Neuroscience volume 16, pages 10491059 (2013) | Download Citation

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.

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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

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

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Pablo E Castillo.

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DOI

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

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