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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Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures

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 8

Absence epilepsy in VB-specific HCN2-KO mice.

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Absence epilepsy in VB-specific HCN2-KO mice. (A) Strategy for specific ...
(A) Strategy for specific deletion of HCN channels in the VB. Left panel: Scheme of the AAV2/8-hSyn-Cre-EGFP vector that was injected stereotactically into the VB of HCNfl/fl mice. The schematic brain shows the injected region in the thalamus. Only cells in the VB show the green EGFP signal due to viral transfection. (B) Staining with anti-HCN2 antibody (red) in the VB region shows that Cre/EGFP–positive neurons (green) lack HCN2, while nontransduced (EGFP-negative) cells express HCN2 in the plasma membrane (marked by white arrows). Scale bar: 5 μm. VM, ventromedial region. (C) VB-specific HCN2-KO mice show SWDs (marked with an asterisk) in EEG traces (representative trace, n = 3). The inset shows a magnification of the SWD. (D) Representative EEG (green) and EMG (black) traces of an HCN2fl/fl mouse that was injected with a control AAV vector that expresses only EGFP (n = 3). (D) Representative EEG (green) and EMG (black) traces of a VB-specific HCN4-KO animal that was generated by injecting the same vector as displayed in Figure 7A into the VB of an HCN4fl/fl mouse (n = 3).