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Activity-dependent decrease of excitability in rat hippocampal neurons through increases in Ih

Nature Neuroscience volume 8, pages 15421551 (2005) | Download Citation

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  • A Corrigendum to this article was published on 01 January 2006

This article has been updated

Abstract

Hippocampal long-term potentiation (LTP) induced by theta-burst pairing of Schaffer collateral inputs and postsynaptic firing is associated with localized increases in synaptic strength and dendritic excitability. Using the same protocol, we now demonstrate a decrease in cellular excitability that was blocked by the h-channel blocker ZD7288. This decrease was also induced by postsynaptic theta-burst firing alone, yet it was blocked by NMDA receptor antagonists, postsynaptic Ca2+ chelation, low concentrations of tetrodotoxin, ω-conotoxin MVIIC, calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors and a protein synthesis inhibitor. Increasing network activity with high extracellular K+ caused a similar reduction of cellular excitability and an increase in h-channel HCN1 protein. We propose that backpropagating action potentials open glutamate-bound NMDA receptors, resulting in an increase in Ih and a decrease in overall excitability. The occurrence of such a reduction in cellular excitability in parallel with synaptic potentiation would be a negative feedback mechanism to normalize neuronal output firing and thus promote network stability.

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  • 14 December 2005

    The PDF version of this article was corrected on December 14, 2005. Please see the PDF for details.

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Acknowledgements

We thank R. Gray, N. Poolos and A. Frick for discussions and help with data acquisition and analysis software. We also thank W.S. She for technical help with western blotting. This work was supported by US NIH grants MH48432, MH44754 and NS37444 (D.J.) and NS48884 and AHA0465158Y (H.-C.L.); a fellowship from the American Heart Association (Y.F.); and a fellowship from the North Atlantic Treaty Organization (D.F.).

Author information

Author notes

    • Yuan Fan
    •  & Desdemona Fricker

    These authors contributed equally to this work.

Affiliations

  1. Center for Learning and Memory, University of Texas at Austin, 1 University Station, C7000, Austin, Texas 78712, USA.

    • Yuan Fan
    • , Darrin H Brager
    • , Xixi Chen
    • , Raymond A Chitwood
    •  & Daniel Johnston
  2. Institut National de la Santé et de la Recherche Médicale (INSERM) U739–Cortex et Epilepsie, Faculté de Médecine Pitié-Salpêtrière, 105 Boulevard de I'Hôpital, 75013 Paris, France.

    • Desdemona Fricker
  3. Cain Foundation Laboratories, Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.

    • Hui-Chen Lu

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel Johnston.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    EPSP-spike transitions at an expanded time scale.

  2. 2.

    Supplementary Fig. 2

    Sag ratio increased after LTP.

  3. 3.

    Supplementary Fig. 3

    TBP-LTP but not 100 Hz-LTP was accompanied by a decrease in RN.

  4. 4.

    Supplementary Fig. 4

    TBF-induced decrease in excitability could be prevented by ZD7288.

  5. 5.

    Supplementary Fig. 5

    Background synaptic inputs were less efficient after TBF.

  6. 6.

    Supplementary Fig. 6

    A brief episode of extracellular high K+ challenge produced a reduction in input resistance similar to TBF.

  7. 7.

    Supplementary Fig. 7

    High extracellular K+ stimulated differential regulation of HCN protein levels.

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DOI

https://doi.org/10.1038/nn1568

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