The hyperpolarization-activated cation current I-h is an important regulator of neuronal excitability and may contribute to the properties of the dentate gyrus granule (DGG) cells, which constitute the input site of the canonical hippocampal circuit. Here, we investigated changes in I-h in DGG cells in human temporal lobe epilepsy (TLE) and the rat pilocarpine model of TLE using the patch-clamp technique. Messenger-RNA (mRNA) expression of I-h-conducting HCN1, 2 and 4 isoforms was determined using semi-quantitative in-situ hybridization. I-h density was similar to 1.8-fold greater in DGG cells of TLE patients with Ammon's horn sclerosis (AHS) as compared to patients without AHS. The magnitude of somatodendritic I-h was enhanced also in DGG cells in epileptic rats, most robustly during the latent phase after status epilepticus and prior to the occurrence of spontaneous epileptic seizures. During the chronic phase, I-h was increased similar to 1.7-fold. This increase of I-h was paralleled by an increase in HCN1 and HCN4 mRNA expression, whereas HCN2 expression was unchanged. Our data demonstrate an epilepsy-associated upregulation of I-h likely due to increased HCN1 and HCN4 expression, which indicate plasticity of I-h during epileptogenesis and which may contribute to a compensatory decrease in neuronal excitability of DGG cells. (C) 2012 Elsevier Inc. All rights reserved.