By using patch-clamp recordings in the dendrites and soma of hippocampal CA1 pyramidal neurons, Poolos et al. found that the anticonvulsant lamotrigine selectively reduced depolarization-induced action potential firing in dendrites. The authors also showed that, in these neurons, H-current is present predominantly in the dendrites, and further, that the impact of lamotrigine on action-potential firing was due to selective augmentation of the conductance. This increase in H-current conductance was caused by a drug-induced shift in the voltage dependence of activation of H-current to more depolarized levels closer to the neuronal resting potential. This study is the first to demonstrate an anticonvulsant targeting H-current. Clearly, this mechanism could be important to the regulation of dendritic excitability in hippocampal neurons, thereby reducing seizures. An additional, obvious implication of these findings is that H-current may be a useful target for future antiepileptic drug (AED) development.

Further support for the concept that H-current may be a viable target for AEDs resulted from a second publication in which Surges et al. demonstrated that another AED, gabapentin, also augmented H-current in CA1 pyramidal neurons when applied at clinically relevant concentrations (i.e., concentrations achieved as free serum levels in patients). The effect was mechanistically distinct from the activation curve shift described by Poolos et al. because gabapentin augmented H-current by increasing the conductance of these channels, with no effects on the voltage dependence of activation. Although other cellular effects of gabapentin have been described, its actions on H-current are most clearly related to a possible antiepileptic action.

A final piece of the puzzle supporting the idea that H-currents may be important new targets for therapeutic intervention for epilepsy came from a series of studies that examined H-current regulation in animal models of epilepsy. H-current is augmented in a number of animal models of epilepsy and hyperexcitability, including a rat febrile seizure model and the stargazer epileptic mouse mutant. A recently published review by Chen et al. summarizes these data (1). Thus, H-current not only may serve as a drug target, but it also may play a role in the underlying disease process of epilepsy.

Clearly, a new concept is beginning to emerge concerning the potential role of H-current as a therapeutic target and player in the development of epilepsy. However, the picture is complex. H-current alone is incapable of generating activity. It acts in concert with other regenerative conductances within neurons, and the relative ensemble of such conductances varies in a cell- and region-specific manner in the brain. Blocking H-current in some areas of the brain (such as thalamus) (2, 3) may have a net anticonvulsant effect, whereas augmenting H-current in other areas (such as hippocampus) may decrease excitability. Further complexities derive from potential interactions between mechanisms determining the underlying disease process of epilepsy. For example, in the febrile seizure model of epilepsy, an augmented H-current in hippocampal area CA1 neurons is evident concurrent with enhanced γ-aminobutyric acid (GABA)ergic inhibition (reviewed in Chen et al.). This interactive combination of events serves to synchronize activity powerfully in this region, contributing to hyperexcitability.