Aberrant HCN4 channel expression: Impacts on neuronal excitability and implications for epilepsy pathogenesis

Hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels are nonselective voltage-gated cation channels encoded by four genes (HCN1-4) that show distinct localisation patterns throughout the central nervous system and body. Among the four isoforms, HCN4 channels are most widely known for their pacemaker activity in cardiac tissue, with HCN4 pathogenic variants being strongly associated with cardiac abnormalities. In the brain, HCN4 channels are predominantly expressed in subcortical regions, where they play roles in regulating brain function including controlling transmitter release, burst firing, and neuronal network oscillatory activity. HCN4 channels also have been proposed as important modulators of general seizure susceptibility. Importantly, accumulating evidence points to HCN4 channel involvement in the aetiology of hyperexcitability in focal cortical dysplasia and tuberous sclerosis. In this review, we have explored the function of HCN4 channels in the brain, focusing on their key roles in modulating both individual neuron and network-level excitability. More specifically, we have examined the canonical functions of HCN4 channels in regulating rhythmic and oscillatory activity. We have discussed the evidence, from both the clinic and animal modelling, linking aberrant HCN4 channel expression with epilepsy, and evaluated the targeting of HCN4 channels as a potential therapeutic strategy for seizure control.