Hyperpolarization-activated cyclic nucleotide-gated channels and epilepsy: genetics, circuits, and treatments

Epilepsy is a common chronic disorder of the central nervous system characterized by recurrent seizures arising from abnormal, hypersynchronous neuronal activity; its pathogenesis is complex and remains incompletely understood. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are a family of voltage-gated ion channels that mediate the hyperpolarization-activated cation current (I h ) and play key roles in regulating neuronal excitability, rhythmic activity, and synaptic transmission. Recent studies indicate that abnormal HCN channel expression, pathogenic genetic variants, or dysregulated protein interactions are closely linked to the onset and progression of epilepsy and may contribute to disease by destabilizing membrane-potential homeostasis, perturbing neurotransmitter balance, and disrupting network-level control of excitability. This review summarizes the structural and functional properties of HCN channels and focuses on their mechanistic roles in epileptogenesis, with the goal of informing clinical diagnosis and therapeutic development.