The Impact of Altered HCN1 Expression on Brain Function and Its Relationship with Epileptogenesis

Hyperpolarization-activated cyclic nucleotide-gated cation channel 1 (HCN1) is predominantly expressed in neurons from the neocortex and hippocampus, two important regions related to epilepsy. Both animal models for epilepsy and epileptic patients show decreased HCN1 expression and HCN1-mediated I_h current. It has been shown in neuroelectrophysiological experiments that a decreased I_h current can increase neuronal excitability. However, some studies have shown that blocking the I_h current in vivo can exert antiepileptic effects. This paradox raises an important question regarding the causal relationship between HCN1 alteration and epileptogenesis, which to date has not been elucidated. In this review, we summarize the literature related to HCN1 and epilepsy, aiming to find a possible explanation for this paradox, and explore the correlation between HCN1 and the mechanism of epileptogenesis. We analyze the alterations in the expression and distribution of HCN1 and the corresponding impact on brain function in epilepsy. In addition, we also discuss the effect of blocking I_h on epilepsy symptoms. Addressing these issues will help to inspire new strategies to explore the relationship between HCN1 and epileptogenesis, and ultimately promote the development of new targets for epilepsy therapy.