Ca2+-dependent large conductance K+ currents in thalamocortical relay neurons of different rat strains

Mutations in genes coding for Ca²⁺ channels were found in patients with childhood absence epilepsy (CAE) indicating a contribution of Ca²⁺-dependent mechanisms to the generation of spike-wave discharges (SWD) in humans. Since the involvement of Ca²⁺ signals remains unclear, the aim of the present study was to elucidate the function of a Ca²⁺-dependent K⁺ channel (BK_Ca) under physiological conditions and in the pathophysiological state of CAE. The activation of BK_Ca channels is dependent on both voltage and intracellular Ca²⁺ concentrations. Moreover, these channels exhibit an outstandingly high level of regulatory heterogeneity that builds the basis for the influence of BK_Ca channels on different aspects of neuronal activity. Here, we analyse the contribution of BK_Ca channels to firing of thalamocortical relay neurons, and we test the hypothesis that BK_Ca channel activity affects the phenotype of a genetic rat model of CAE. We found that the activation of the β₂-adrenergic receptor/protein kinase A pathway resulted in BK_Ca channel inhibition. Furthermore, BK_Ca channels affect the number of action potentials fired in a burst and produced spike frequency adaptation during tonic activity. The latter result was confirmed by a computer modelling approach. We demonstrate that the β₂-adrenergic inhibition of BK_Ca channels prevents spike frequency adaptation and, thus, might significantly support the tonic firing mode of thalamocortical relay neurons. In addition, we show that BK_Ca channel functioning differs in epileptic WAG/Rij and thereby likely contributes to highly synchronised, epileptic network activity.