Increased seizure severity and seizure‐related death in mice lacking HCN1 channels

Abstract

SUMMARYPersistent down-regulation in the expression of the hyperpolarization-activated HCN1 cation channel, a key determinant of intrinsic neuronal excitability, has been observed in febrile seizure, temporal lobe epilepsy, and generalized epilepsy animal models, as well as in patients with epilepsy. However, the role and importance of HCN1 down-regulation for seizure activity is unclear. To address this question we determined the susceptibility of mice with either a general or forebrain-restricted deletion of HCN1 to limbic seizure induction by amygdala kindling or pilocarpine administration. Loss of HCN1 expression in both mouse lines is associated with higher seizure severity and higher seizure-related mortality, independent of the seizure-induction method used. Therefore, down-regulation of HCN1 associated with human epilepsy and rodent models may be a contributing factor in seizure behavior.

Effect of low frequency repetitive transcranial magnetic stimulation on kindling-induced changes in electrophysiological properties of rat CA1 pyramidal neurons

“…However, the role of HCN disorders in epilepsy is complex. Studies in experimental models indicate that both up-regulation (Dyhrfjeld-Johnsen et al, 2008;Gill et al, 2006) and down-regulation (Powell et al, 2008;Richichi et al, 2008;Santoro et al, 2010;Shah et al, 2004;Strauss et al, 2004) of HCN channels can be associated with seizures. Our Q5 data were clearly inconsistent with an increase in I h current during the neuronal hyperexcitability in CA1 region of the hippocampus.…”

Corticospinal-specific HCN expression in mouse motor cortex: Ih-dependent synaptic integration as a candidate microcircuit mechanism involved in motor control

“…Expression levels were quantified for HCN1 and HCN2 genes, the major isoforms expressed in brain (Moosmang et al 1999;Notomi and Shigemoto 2004;Santoro et al 2010), and referenced to GAPDH expression levels (Chan et al 2011). We also probed for Trip8b, a protein involved in trafficking of HCN subunits to dendritic membranes, including establishment of somatodendritic HCN1 channel gradients (Lewis et al 2009;Lewis et al 2011;Santoro et al 2004Santoro et al , 2009.…”

Origins of Temporal Lobe Epilepsy: Febrile Seizures and Febrile Status Epilepticus

“…For example, the transient-receptor-potential vanilloid (TRPV) 1 and 4 channels are regulated by brain temperature in the physiological and fever ranges, and have been implicated in febrile seizures in animal models [49] where elevated brain temperature leads to augmented neuronal firing, facilitating seizures. Similarly, HCN channels [22,50] and Cav1.2 calcium channels [51] seem to contribute to the hyperexcitability that results in febrile seizures. In children, increased temperature per se, resulting from hot baths or anticholinergics overdose, may lead to seizures [52], but the mechanisms are likely multifactorial [53] and remain obscure.…”