Trafficking mechanism of H channels in CA1 pyramidal neurons and its implication in the pathophysiology of temporal lobe epilepsyPublic Deposited
Many ion channels are localized in specific subcellular domain of the neurons, and the proper localization is critical for the function of ion channels. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (h channels) are asymmetrically distributed in the CA1 pyramidal neurons, enriched in the distal apical dendrites. H current, generated by h channels, plays an important role in maintaining the neuronal excitability in the dendrites of CA1 pyramidal neurons. Moreover, abnormal Ih in hippocampus has been suggested as a pathophysiological mechanism in animal models of temporal lobe epilepsy (TLE). Although the unique distribution pattern of h channels is considered crucial for their function, it has been poorly understood how h channels are targeted to the distal dendrites and whether trafficking of h channels is altered during the epileptogenesis. In this study, we found that distal dendritic localization of h channel subunit, HCN1, is regulated by neuronal activity through the direct input from the entorhinal cortex (EC) in the cultured hippocampal slices. Next, we identified HCN2 null mice, apathetic, and found loss of h channels increases the severity to the generalized seizures. At last, using the kainic acid (KA)-induced animal model of TLE, we found that h channel is augmented in distal stratum radiatum of CA1 area hippocampus in early latent period. By the onset of spontaneous recurring seizure, HCN1 are lost from the distal dendrites and redistributed to the soma in CA1 pyramidal neurons. Redistribution of h channels is likely due to the loss of interaction with the h channel-interacting protein, TRIP8b. Taken together, in this study, we demonstrate that h channel localization is regulated by neuronal activity, as a part of homeostatic mechanism to maintain the cellular excitability, and the loss of proper h channel trafficking during the epileptogenesis may be an important pathophysiological mechanism for development of TLE. Thus, our study provides more clues to elucidate the detailed pathophysiological mechainsm of TLE and find the therapeutic targets to prevent the development of TLE.