Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized 
seizures

Hammelmann, Verena; Stieglitz, Marc Sebastian; Huelle, Henrik; Le Meur, Karim; Kass, Jennifer; Bruemmer, Manuela; Gruner, Christian; Roetzer, Rene Dominik; Fenske, Stefanie; Hartmann, Jana; Zott, Benedikt; Luthi, Anita; Spahn, Saskia; Moser, Markus; Isbrandt, Dirk; Ludwig, Andreas; Konnerth, Arthur; Wahl-Schott, Christian; Biel, Martin

doi:10.1172/jci.insight.126418

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Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures

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Moser, Markus
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Hammelmann, V., Stieglitz, M. S., Huelle, H., Le Meur, K., Kass, J., Bruemmer, M., et al. (2019). Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures. JCI Insight, 4(9): e126418. doi:10.1172/jci.insight.126418.

Cite as: https://hdl.handle.net/21.11116/0000-0003-E133-5

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually gated channels that are operated by voltage and by neurotransmitters via the cAMP system. cAMP-dependent HCN regulation has been proposed to play a key role in regulating circuit behavior in the thalamus. By analyzing a knockin mouse model (HCN2EA), in which binding of cAMP to HCN2 was abolished by 2 amino acid exchanges (R591E, T592A), we found that cAMP gating of HCN2 is essential for regulating the transition between the burst and tonic modes of firing in thalamic dorsal-lateral geniculate (dLGN) and ventrobasal (VB) nuclei. HCN2EA mice display impaired visual learning, generalized seizures of thalamic origin, and altered NREM sleep properties. VB-specific deletion of HCN2, but not of HCN4, also induced these generalized seizures of the absence type, corroborating a key role of HCN2 in this particular nucleus for controlling consciousness. Together, our data define distinct pathological phenotypes resulting from the loss of cAMP-mediated gating of a neuronal HCN channel.