부산대학교 도서관

Hyperpolarization activated cyclic nucleotide-gated (HCN) channel 1 is abundantly expressed in cerebral cortex, hippocampus, and cerebellum, regulating spontaneous rhythm and neural oscillation. Previous study reported that human mutations in the HCN1 gene are associated with early infantile epileptic encephalopathy and genetic generalized epilepsy (Brain, 141, 3160-3178, 2018), however, the functional mechanism underlying seizure generation is still unknown. In this study, we examined the effects of HCN1 channel inhibitor (ZD7288) and the HCN1 gene deletion on pilocarpine-induced seizure to elucidate the role of HCN1 channel in modulating seizure susceptibility. Treatment of mice with ZD7288 significantly increased the incidence of status epilepticus and the frequency of seizures as compared with control mice. Hcn1-KO rats showed a higher seizure susceptibility to pilocarpine than control (F344) rats. Thus, pilocarpine elicited status epilepticus in all Hcn1-KO rats tested, but in none of control rats. In addition, we performed the immunohistochemical analysis of c-Fos expression following pilocarpine-induced seizure. Hcn1-KO rats showed a significantly higher c-Fos expression than control rats, notably in the cerebral cortex and amygdala. These results suggest that HCN1 channels play an important role in modulating the susceptibility to epileptic seizures, implying that dysfunction of HCN1 channels cause neuronal hyperactivation of the cerebral cortex and amygdala.