Formation of heteromeric hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the hippocampus is regulated by developmental seizures.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate hyperpolarization-activated currents (I(h)). In hippocampus, these currents contribute greatly to intrinsic cellular properties and synchronized neuronal activity. The kinetic and gating properties of HCN-mediated currents are largely determined by the type of subunits--for example, HCN1 and HCN2--that assemble to form homomeric channels. Recently, functional heteromeric HCN channels have been described in vitro, further enlarging the potential I(h) repertoire of individual neurons. Because these heteromeric HCN channels may promote hippocampal hyperexcitability and the development of epilepsy, understanding the mechanisms governing their formation is of major clinical relevance. Here, we find that developmental seizures promote co-assembly of hippocampal HCN1/HCN2 heteromeric channels, in a duration-dependent manner. Long-lasting heteromerization was found selectively after seizures that provoked persistent hippocampal hyperexcitability. The mechanism for this enhanced heteromerization may involve increased relative abundance of HCN2-type subunits relative to the HCN1 isoform at both mRNA and protein levels. These data suggest that heteromeric HCN channels may provide molecular targets for intervention in the epileptogenic process.