Cellular and Molecular Life Sciences

, Volume 68, Issue 1, pp 125–137 | Cite as

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

  • Lucas Matt
  • Stylianos Michalakis
  • Franz Hofmann
  • Verena Hammelmann
  • Andreas Ludwig
  • Martin Biel
  • Thomas KleppischEmail author
Research Article


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.


Hippocampus Long-term potentiation Oriens-lacunosum moleculare interneurons Perforant path HCN channel 



Hyperpolarization-activated cyclic nucleotide-gated channels


Long-term potentiation


Oriens-lacunosum moleculare interneuron


Direct perforant pathway


Schaffer collateral pathway



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).

Supplementary material

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Supplementary material 1 (PDF 313 kb)
18_2010_446_MOESM2_ESM.pdf (81 kb)
Supplementary material 2 (PDF 82 kb)
18_2010_446_MOESM3_ESM.pdf (168 kb)
Supplementary material 3 (PDF 168 kb)
18_2010_446_MOESM4_ESM.pdf (72 kb)
Supplementary material 4 (PDF 72 kb)


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Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Lucas Matt
    • 1
  • Stylianos Michalakis
    • 2
    • 5
  • Franz Hofmann
    • 1
    • 4
    • 5
  • Verena Hammelmann
    • 2
    • 5
  • Andreas Ludwig
    • 3
  • Martin Biel
    • 2
    • 5
  • Thomas Kleppisch
    • 1
    Email author
  1. 1.Institut für Pharmakologie und Toxikologie der Technischen Universität MünchenMunichGermany
  2. 2.Department of Pharmacy, Center for Drug ResearchLudwig-Maximilians-Universität MünchenMunichGermany
  3. 3.Institut für Experimentelle und Klinische Pharmakologie und ToxikologieFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  4. 4.DFG Forschergruppe 932MunichGermany
  5. 5.Munich Center for Integrated Protein Science CIPSMMunichGermany

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