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HCN2 channels in local inhibitory interneurons constrain LTP in the hippocampal direct perforant path

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Abstract

Neuronal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to modulate spontaneous activity, resting membrane potential, input resistance, afterpotential, rebound activity, and dendritic integration. To evaluate the role of HCN2 for hippocampal synaptic plasticity, we recorded long-term potentiation (LTP) in the direct perforant path (PP) to CA1 pyramidal cells. LTP was enhanced in mice carrying a global deletion of the channel (HCN2−/−) but not in a pyramidal neuron-restricted knockout. This precludes an influence of HCN2 located in postsynaptic pyramidal neurons. Additionally, the selective HCN blocker zatebradine reduced the activity of oriens-lacunosum moleculare interneurons in wild-type but not HCN2−/− mice and decreased the frequency of spontaneous inhibitory currents in postsynaptic CA1 pyramidal cells. Finally, we found amplified LTP in the PP of mice carrying an interneuron-specific deletion of HCN2. We conclude that HCN2 channels in inhibitory interneurons modulate synaptic plasticity in the PP by facilitating the GABAergic output onto pyramidal neurons.

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Abbreviations

HCN:

Hyperpolarization-activated cyclic nucleotide-gated channels

LTP:

Long-term potentiation

O-LM:

Oriens-lacunosum moleculare interneuron

PP:

Direct perforant pathway

SC:

Schaffer collateral pathway

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Acknowledgments

The authors thank John L. Rubenstein and Marc Ekker for providing the Dlx5/6-Cre mouse line. This work was supported by a grant from the Deutsche Forschungsgemeinschaft to Thomas Kleppisch (KL1172/2-4).

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Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie der Technischen Universität München, Biedersteiner Straße 29, 80802, Munich, Germany

    Lucas Matt, Franz Hofmann & Thomas Kleppisch

  2. Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 7, 81377, Munich, Germany

    Stylianos Michalakis, Verena Hammelmann & Martin Biel

  3. Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054, Erlangen, Germany

    Andreas Ludwig

  4. DFG Forschergruppe 932, Munich, Germany

    Franz Hofmann

  5. Munich Center for Integrated Protein Science CIPSM, Butenandtstr. 7, 81377, Munich, Germany

    Stylianos Michalakis, Franz Hofmann, Verena Hammelmann & Martin Biel

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  1. Lucas Matt
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  2. Stylianos Michalakis
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  7. Thomas Kleppisch
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Correspondence to Thomas Kleppisch.

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Matt, L., Michalakis, S., Hofmann, F. et al. HCN2 channels in local inhibitory interneurons constrain LTP in the hippocampal direct perforant path. Cell. Mol. Life Sci. 68, 125–137 (2011). https://doi.org/10.1007/s00018-010-0446-z

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  • DOI: https://doi.org/10.1007/s00018-010-0446-z

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