Gene expression of the HCN family in rats with pilocarpine-induced epilepsy and in human hippocampal and cortical tissue.

BACKGROUND

Epilepsy is a chronic pathophysiological syndrome defined by excessive and recurrent neuronal electrical discharges in the brain, affecting approximately 0.8% of the global population. The concept of channelopathy emerges as a fundamental basis for this dysfunction, involving failures in voltage-gated ion channels. Among these, hyperpolarization-activated cation channels (HCN), encoded by the HCN1-4 genes, are unique due to their pacemaker function and sensitivity to abnormal electrical activity, regulating resting membrane potential and neuronal excitability.

METHODS

The expression of HCN1-HCN4 genes was analyzed in experimental and human models of epilepsy. Male Wistar rats were assigned to control and pilocarpine-induced epilepsy groups, representing the acute and chronic phases of the disease. Following the induction of status epilepticus, regions of the central nervous system, including hippocampal subfields, temporal cortex, and cerebellum, were collected for molecular analysis. Human hippocampal tissue was obtained from patients with pharmacoresistant temporal lobe epilepsy undergoing surgery, while samples from patients with traumatic brain injury were used as controls. Gene expression was quantified by real-time PCR using specific primers, and data were analyzed using the 2-ΔΔCT method, normalized to β-actin, with statistical significance set at P < 0.05.

RESULTS

HCN1-4 transcripts were detected in all analyzed regions of the rat and human central nervous system. In control rats, HCN1 was the predominant subtype across hippocampal, cortical, and cerebellar regions. Acute pilocarpine-induced epilepsy was associated with minimal changes in HCN expression patterns. In contrast, chronic epilepsy resulted in a marked, region-specific downregulation of HCN1 and HCN2, particularly in hippocampal and neocortical areas. Human hippocampal and cortical tissues exhibited a similar expression profile, with HCN1 predominance in controls and altered relative expression in epileptic samples, supporting conserved epilepsy-related remodeling of HCN channel expression.

CONCLUSIONS

Our results support previous finding and further suggest unexpected actions of CHCNs in the brain and indicate that HCN isoforms is dynamically regulated in human as well as in experimental models of hippocampal epilepsy, suggesting also that transcriptional dysregulation of HCN might contribute to the epileptogenic process and that certain mechanisms for the altered expression of HCN channels may be involved in the epileptogenic mechanisms.