Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures
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
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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Research Article Neuroscience

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 3

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) Representative Ih traces from thalamocortical WT (upper) and HCN2EA neurons (lower) in the VB. Below, voltage protocol used to evoke current traces. (B) Ih density of thalamocortical neurons in the dLGN (HCN2EA, red squares [n = 13]; WT, gray squares [n = 11]; P = 0.3524 by Mann-Whitney test) and the VB (HCN2EA, blue squares [n = 4]; WT, gray squares [n = 6]; P = 0.6021 by Mann-Whitney test). NS, not significant. (C) Normalized current-voltage relationships of Ih in thalamocortical neurons of WT and HCN2EA mice in the absence (–cAMP) and presence of 1 μM cAMP (Boltzmann fit). Upper left: dLGN, HCN2EA: solid red line, –cAMP (n = 6); dashed red line, +cAMP (n = 4). Upper right: dLGN, WT: solid gray line, –cAMP (n = 6); dashed gray line, +cAMP (n = 5). Lower left: VB, HCN2EA: solid blue line, –cAMP (n = 4); dashed blue line, +cAMP (n = 5). Lower right: VB, WT: solid gray line, –cAMP (n = 6); dashed gray line, +cAMP (n = 8). The cAMP-dependent shift of the midpoint potentials (V0.5) of activation is indicated as dashed black lines.