ABSTRACT
Aberrant function of pacemaker currents (Ih), carried by hyperpolarization-activated cation non-selective (HCN) channels, affects neuronal excitability and accompanies epilepsy, but its distinct roles in epileptogenesis and chronic epilepsy are unclear. We probed Ih function and subunit composition during both pre- and chronically epileptic stages in thalamocortical (TC) neurones of the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Voltage gating of Ih was unaltered in mature somatosensory TC cells, both in vivo and in vitro. However, the enhancement of Ih by phasic, near-physiological, cAMP pulses was diminished by approximately 40% and the half-maximal cAMP concentration increased by approximately 5-fold. This decreased responsiveness of Ih to its major cellular modulator preceded epilepsy onset in GAERS, persisted throughout the chronic state, and was accompanied by an enhanced expression of the cAMP-insensitive HCN1 channel mRNA (> 50%), without changes in the mRNA levels of HCN2 and HCN4. To assess for alterations in TC cell excitability, we monitored the slow up-regulation of Ih that is induced by Ca2+-triggered cAMP synthesis and important for terminating in vitro synchronized oscillations. Remarkably, repetitive rebound Ca2+ spikes evoked normal slow Ih up-regulation in mature GAERS neurones; that sufficed to attenuate spontaneous rhythmic burst discharges. These adaptive mechanisms occurred upstream of cAMP turnover and involved enhanced intracellular Ca2+ accumulation upon repetitive low-threshold Ca2+ discharges. Therefore, HCN channels appear to play a dual role in epilepsy. Weakened cAMP binding to HCN channels precedes, and likely promotes, epileptogenesis in GAERS, whereas compensatory mechanisms stabilizing Ih function contribute to the termination of spike-and-wave discharges in chronic epilepsy.
Subject(s)
Biological Clocks , Cerebral Cortex/physiology , Epilepsy, Absence/metabolism , Ion Channels/biosynthesis , Thalamus/physiology , Animals , Calcium/metabolism , Cerebral Cortex/metabolism , Cyclic AMP/metabolism , Cyclic Nucleotide-Gated Cation Channels , Epilepsy, Absence/genetics , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels , Ion Channel Gating , Ion Channels/genetics , Male , Membrane Potentials , Neurons/metabolism , Potassium Channels , RNA, Messenger/biosynthesis , Rats , Rats, Mutant Strains , Rats, Wistar , Thalamus/metabolismABSTRACT
Ionic currents generated by hyperpolarization-activated cation-nonselective (HCN) channels have been principally known as pacemaker h-currents (Ih), because they allow cardiac and neuronal cells to be rhythmically active over precise intervals of time. Presently, these currents are implicated in numerous additional cellular functions, including neuronal integration, synaptic transmission, and sensory reception. These roles are accomplished by virtue of the regulation of Ih by both voltage and ligands. The article summarizes recent developments on the properties and allosteric interactions of these two regulatory pathways in cloned and native channels. Additionally, it discusses how the expression and properties of native channels may be controlled via regulation of the transcription of the HCN channel gene family and the assembly of channel subunits. Recently, several cardiac and neurological diseases were found to be intimately associated with a dysregulation of HCN gene transcription, suggesting that HCN-mediated currents may be involved in the pathophysiology of excitable systems. As a starting point, we briefly review the general characteristics of Ih and the regulatory mechanisms identified in heterologously expressed HCN channels.
