Title: Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2.

Authors: Andreas Ludwig, Thomas Budde, Juliane Stieber, Sven Moosmang, Christian Wahl, Knut Holthoff, Anke Langebartels, Carsten Wotjak, Thomas Munsch, Xiangang Zong, Susanne Feil, Robert Feil, Marike Lancel, Kenneth R Chien, Arthur Konnerth, Hans-Christian Pape, Martin Biel, Franz Hofmann

Journal, date & volume: EMBO J., 2003 Jan 15 , 22, 216-24

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12514127

Abstract
Hyperpolarization-activated cation (HCN) channels are believed to be involved in the generation of cardiac pacemaker depolarizations as well as in the control of neuronal excitability and plasticity. The contributions of the four individual HCN channel isoforms (HCN1-4) to these diverse functions are not known. Here we show that HCN2-deficient mice exhibit spontaneous absence seizures. The thalamocortical relay neurons of these mice displayed a near complete loss of the HCN current, resulting in a pronounced hyperpolarizing shift of the resting membrane potential, an altered response to depolarizing inputs and an increased susceptibility for oscillations. HCN2-null mice also displayed cardiac sinus dysrhythmia, a reduction of the sinoatrial HCN current and a shift of the maximum diastolic potential to hyperpolarized values. Mice with cardiomyocyte- specific deletion of HCN2 displayed the same dysrhythmia as mice lacking HCN2 globally, indicating that the dysrhythmia is indeed caused by sinoatrial dysfunction. Our results define the physiological role of the HCN2 subunit as a major determinant of membrane resting potential that is required for regular cardiac and neuronal rhythmicity.