Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Ion Channelopathy in Epilepsy

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) voltage-gated ion channels are widely expressed in cortex, hippocampus, and thalamus, brain regions that underlie the generation of both focal and generalized-onset seizures. Greater understanding of the contribution of HCN channel function to neuronal physiology has been paralleled by increasing evidence for their role in epilepsy. Genetic deletion of the HCN2 channel subtype leads to an absence epilepsy phenotype, while deletion of the HCN1 subtype produces hypersensitivity to provoked seizures and accelerates epileptogenesis. Pharmacological blockade of HCN channels likewise produces neuronal hyperexcitability, while one or more antiepileptic drugs appear to upregulate HCN channel function. In animal models of acquired epilepsy, loss of HCN channel expression and function occurs during the earliest phases of epileptogenesis, and promotes the occurrence of seizures. Thus, numerous lines of evidence point to a role for HCN channels in epilepsy, especially in acquired syndromes. In this chapter, I describe how the biophysical properties of HCN channels position them to play a significant role in epileptogenesis; how emerging evidence suggests the existence of HCN channelopathy in human epilepsy; and how the mechanisms underlying HCN channelopathy could be targeted in antiepileptic therapies.