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Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures
Verena Hammelmann, … , Christian Wahl-Schott, Martin Biel
Verena Hammelmann, … , Christian Wahl-Schott, Martin Biel
Published May 2, 2019
Citation Information: JCI Insight. 2019;4(9):e126418. https://doi.org/10.1172/jci.insight.126418.
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Research Article Neuroscience

Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures

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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.

Authors

Verena Hammelmann, Marc Sebastian Stieglitz, Henrik Hülle, Karim Le Meur, Jennifer Kass, Manuela Brümmer, Christian Gruner, René Dominik Rötzer, Stefanie Fenske, Jana Hartmann, Benedikt Zott, Anita Lüthi, Saskia Spahn, Markus Moser, Dirk Isbrandt, Andreas Ludwig, Arthur Konnerth, Christian Wahl-Schott, Martin Biel

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Figure 1

Impaired modulation of Ih by cAMP in thalamocortical neurons expressing HCN2EA.

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Impaired modulation of Ih by cAMP in thalamocortical neurons expressing ...
(A) Structural model of the CNBD of HCN channels. The 2 key residues R591 (yellow) and T592 (pink) that are crucial for binding of cAMP are highlighted. (B) Horizontal brain slices of WT and HCN2EA mice. The position of the dLGN (red) and the VB (blue) is indicated. (C) Detection of HCN2 and HCN4 in Western blot analysis of punched dLGN and VB regions. Images are representatives of n = 3/group. (D) Western blot analysis of membrane preparations of HCN2EA and WT mice probed for HCN2 and a loading control (Na+/K+-ATPase). Images are representatives of n = 3/group. (E) Quantification of HCN2 expression level in relation to the Na+/K+-ATPase (n = 3).

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