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

Nature Neuroscience volume 8, pages 1542–1551 (2005)Cite this article

A Corrigendum to this article was published on 01 January 2006

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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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Figure 1: TBP-induced LTP was accompanied by a decrease in input resistance (RN).
Figure 2: TBP-LTP was associated with a persistent decrease in excitability.
Figure 3: Blockade of h-channels reversed and occluded the decrease in excitability without affecting LTP of EPSPs.
Figure 4: Theta-burst firing (TBF) alone sufficed to produce a decrease in excitability.
Figure 5: Decreased excitability required postsynaptic Ca2+ and NMDA-receptor activation.
Figure 6: Backpropagating action potentials were necessary for a TBF-induced decrease in excitability.
Figure 7: Spontaneous glutamate release was required for TBF-induced decrease in excitability.
Figure 8: CaMKII and de novo protein synthesis were required for the TBP- and TBF-induced decrease in excitability.

Change history

  • 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.).

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Author notes

  1. Yuan Fan and Desdemona Fricker: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Learning and Memory, University of Texas at Austin, 1 University Station, C7000, Austin, 78712, Texas, 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, Paris, 75013, France

    Desdemona Fricker

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

    Hui-Chen Lu

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Correspondence to Daniel Johnston.

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Supplementary information

Supplementary Fig. 1

EPSP-spike transitions at an expanded time scale. (PDF 238 kb)

Supplementary Fig. 2

Sag ratio increased after LTP. (PDF 372 kb)

Supplementary Fig. 3

TBP-LTP but not 100 Hz-LTP was accompanied by a decrease in RN. (PDF 683 kb)

Supplementary Fig. 4

TBF-induced decrease in excitability could be prevented by ZD7288. (PDF 1244 kb)

Supplementary Fig. 5

Background synaptic inputs were less efficient after TBF. (PDF 769 kb)

Supplementary Fig. 6

A brief episode of extracellular high K+ challenge produced a reduction in input resistance similar to TBF. (PDF 1496 kb)

Supplementary Fig. 7

High extracellular K+ stimulated differential regulation of HCN protein levels. (PDF 1724 kb)

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Fan, Y., Fricker, D., Brager, D. et al. Activity-dependent decrease of excitability in rat hippocampal neurons through increases in Ih. Nat Neurosci 8, 1542–1551 (2005). https://doi.org/10.1038/nn1568

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