TY - JOUR AU - Hammelmann, Verena AU - Stieglitz, Marc Sebastian AU - Hülle, Henrik AU - Le Meur, Karim AU - Kass, Jennifer AU - Brümmer, Manuela AU - Gruner, Christian AU - Rötzer, René Dominik AU - Fenske, Stefanie AU - Hartmann, Jana AU - Zott, Benedikt AU - Lüthi, Anita AU - Spahn, Saskia AU - Moser, Markus AU - Isbrandt, Dirk AU - Ludwig, Andreas AU - Konnerth, Arthur AU - Wahl-Schott, Christian AU - Biel, Martin T1 - Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures PY - 2019/05/02/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.126418 VL - 4 IS - 9 UR - https://doi.org/10.1172/jci.insight.126418 PB - The American Society for Clinical Investigation ER -