Progressive Dendritic HCN Channelopathy during Epileptogenesis in the Rat Pilocarpine Model of Epilepsy

Abstract

Ion channelopathy plays an important role in human epilepsy with a genetic cause and has been hypothesized to occur in epilepsy after acquired insults to the CNS as well. Acquired alterations of ion channel function occur after induction of status epilepticus (SE) in animal models of epilepsy, but it is unclear how they correlate with the onset of spontaneous seizures. We examined the properties of hyperpolarization-activated cation (HCN) channels in CA1 hippocampal pyramidal neurons in conjunction with video-EEG (VEEG) recordings to monitor the development of spontaneous seizures in the rat pilocarpine model of epilepsy. Our results showed that dendritic HCN channels were significantly downregulated at an acute time point 1 week postpilocarpine, with loss of channel expression and hyperpolarization of voltage-dependent activation. This downregulation progressively increased when epilepsy was established in the chronic period. Surprisingly, VEEG recordings during the acute period showed that a substantial fraction of animals were already experiencing recurrent seizures. Suppression of these seizures with phenobarbital reversed the change in the voltage dependence of I h , the current produced by HCN channels, but did not affect the loss of HCN channel expression. These results suggest two mechanisms of HCN channel downregulation after SE, one dependent on and one independent of recurrent seizures. This early and progressive downregulation of dendritic HCN channel function increases neuronal excitability and may be associated with both the process of epileptogenesis and maintenance of the epileptic state.

Recessive Loss-of-Function Mutation in the Pacemaker HCN2 Channel Causing Increased Neuronal Excitability in a Patient with Idiopathic Generalized Epilepsy

“…Several studies suggest that downregulation of I h can be proepileptogenic (Peng et al, 2010). In a rat chemoconvulsant (pilocarpine) model of epilepsy, dendritic HCN channels of CA1 hippocampal neurons were substantially downregulated (Jung et al, 2007); interestingly, the activation curve of I h recorded from postpilocarpine CA1 pyramidal neuron dendrites was more negative than in sham animals, similar to the effect we have observed with E515K channels (Figs. 3, 5).…”

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

“…The notion that acquired channelopathies may develop in the course of temporal lobe epilepsy is supported for recent findings in the pilocarpine model of epilepsy (Bernard et al, 2004;Dyhrfjeld-Johnsen and Soltesz, 2004;Hirose, 2006;Jung et al, 2007;Poolos, 2005;Richichi et al, 2007). For instance, it was recently reported that a progressive transcriptional channelopaty ("downregulation") of hyperpolarization-activated cation (HCN) channels occurs in dendrites of CA1 hippocampal pyramidal neurons after pilocarpine-induced SE (Jung et al, 2007). These authors suggest that such deficit in HCN expression and function may increase neuronal excitability and may be associated with both the process of epileptogenesis and maintenance of the epileptic state.…”

“…It remains to be elucidated whether such dysregulation on a subset of ion channels is cause by a seizure-induced long-lasting deficiency of the transcriptional/translational machinery and whether these changes may lead to enhanced excitability of neuronal networks. The notion that acquired channelopathies may develop in the course of temporal lobe epilepsy is supported for recent findings in the pilocarpine model of epilepsy (Bernard et al, 2004;Dyhrfjeld-Johnsen and Soltesz, 2004;Hirose, 2006;Jung et al, 2007;Poolos, 2005;Richichi et al, 2007). For instance, it was recently reported that a progressive transcriptional channelopaty ("downregulation") of hyperpolarization-activated cation (HCN) channels occurs in dendrites of CA1 hippocampal pyramidal neurons after pilocarpine-induced SE (Jung et al, 2007).…”

Epigenetic Mechanisms in Stroke and Epilepsy

“…Disruption of REST binding to the hcn1 promoter by means of decoy oligodeoxynucleotides prevented hcn1 repression and restored its ability to maintain normal levels of dendritic excitability. Collectively, these studies indicate that REST is causally related to HCN1 repression, decreased dendritic excitability, and enhanced epileptiform activity in entorhinal cortical layer III pyramidal neurons (Shah et al, 2004;Jung et al, 2007Jung et al, , 2011 (Figure 1b).…”