Towards an integrated view of HCN channel role in epilepsy

Epilepsy is the third most common brain disorder and affects millions of people. Epilepsy is characterized by the occurrence of spontaneous seizures, that is, bursts of synchronous firing of large populations of neurons. These are believed to result from abnormal regulation of neuronal excitability that favors hypersynchrony. Among the intrinsic conductances that govern neuronal excitability, the hyperpolarization-activated current (Ih) plays complex and important roles in the fine-tuning of both cellular and network activity. Not surprisingly, dysregulation of Ih and/or of its conducting ion-channels (HCN) has been strongly implicated in various experimental models of epilepsy, as well as in human epilepsy. Here we provide an overview of recent findings on the distinct physiological roles played by Ih in specific contexts, and the cellular mechanisms that underlie these functions, including the subunit make-up of the channels. We further discuss current knowledge of dysregulation of Ih and HCN channels in epilepsy in light of the multifaceted functions of Ih in the brain.

► The hyperpolarization activated current Ih plays complex and important roles in fine-tuning cellular and network activity.
► Ih roles depend on HCN subunit makeup, interacting molecules, subcellular location and context/synaptic input.
► Ih dysregulation in epilepsy occurs at many levels and time-frames with complex effects on excitability.
► Understanding Ih will clarify HCN channels’ role as molecular targets in epilepsy.