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

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-de®cient 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 cardiomyocytespeci®c deletion of HCN2 displayed the same dysrhythmia as mice lacking HCN2 globally, indicating that the dysrhythmia is indeed caused by sinoatrial dysfunction. Our results de®ne the physiological role of the HCN2 subunit as a major determinant of membrane resting potential that is required for regular cardiac and neuronal rhythmicity.

Immunohistochemical localization of Ih channel subunits, HCN1–4, in the rat brain

“…1). The HCN1 and HCN2 antibodies labeled broad bands with a molecular mass of 120 kDa consistent with the previous studies (Lorincz et al, 2002;Ludwig et al, 2003). The HCN3 and HCN4 antibodies gave rise to broad bands around molecular masses of 85 and 140 kDa, respectively, which are consistent with the previous study (Muller et al, 2003).…”

“…The HCN4 mRNA is strongly expressed in the mitral cell layer of the olfactory bulb, anterodorsal, laterodorsal, ventroposterior nuclei of the thalamus, and medial habenular nucleus (Monteggia et al, 2000;Santoro et al, 2000;Ludwig et al, 2003). Consistent with these studies, we found very 32 intense HCN4-LI in the thalamic nuclei, but not in the mitral cell layer and medial habenular nucleus.…”

“…Recently, it is reported that in the dorsal lateral geniculate nucleus, thalamocortical neurons of HCN2-deficient mice show a strong reduction of I h , suggesting that I h in thalamocortical cells is predominantly generated by 33 HCN2 (Ludwig et al, 2003). In the present study, prominent immunoreactivity for HCN4 as well as HCN2 was detected in most thalamic nuclei including the lateral geniculate nucleus.…”

“…Relationships between HCN localization and electrophysiological function I h has been identified in numerous cell types in the brain, including neurons in the olfactory bulb (Cadetti and Belluzzi, 2001), neocortex (Berger et al, 2001), hippocampus (Magee, 1999), caudate putamen (Momiyama and Koga, 2001), amygdala (Womble and Moises, 1993), nucleus of accumbens (Uchimura et al, 1990), thalamus (Ludwig et al, 2003), hypothalamus (Kamondi and Reiner, 1991), ventral tegmental area (Jiang et al, 1993), superior colliculus (Saito and Isa, 1999), substantia nigra (Washio et al, 1999), mesencephalic trigeminal nucleus (Khakh and Henderson, 1998), inferior olivary complex , dorsal raphe (Jolas et al, 2000), lateral lemniscus (Fu et al, 1997), area postrema (Funahashi et al, 2002), nucleus of the solitary tract (Iwahori et al, 2002), hypoglossal nucleus (Parkis and Berger, 1997) and cerebellum (Li et al, 1993;Dieudonne, 1998). In the present study, all of these regions showed one or more HCN-LIs.…”

Molecular Targets for Antiepileptic Drug Development

“…In mice, deletion of the HCN2 subunit produces animals with 5-Hz spike-and-wave discharges and absence-like seizures. 163 The WAG/Rij rat model of ab-sence epilepsy shows a loss of HCN1 function in the cortex 164 (possibly linked to the origin of cortical spikeand-wave discharges) but enhanced HCN1 expression in the thalamus. 165 In addition, changes in I h and in HCN subunit expression have been observed in epileptogenesis.…”