Ca2+-dependent large conductance K+ currents in thalamocortical relay neurons of different rat strains
Ca2+-dependent large conductance K+ currents in thalamocortical relay neurons of different rat strains
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DOI：
10.1007/s00424-012-1188-6
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发表时间：
2013-04-01
影响因子：
4.5
通讯作者：
Budde, Thomas
中科院分区：
文献类型：
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作者：
Ehling, Petra;Cerina, Manuela;Budde, Thomas
在儿童失神癫痫(CAE)患者中发现了编码钙离子通道的基因突变，这表明钙依赖机制在人类棘波放电(SWD)的产生中起到了作用。由于钙信号的参与尚不清楚，本研究的目的是阐明钙依赖的钾通道(BKCa)在生理条件和CAE病理生理状态下的功能。BKCa通道的激活依赖于电压和细胞内钙离子浓度。此外，这些通道表现出非常高的调控异质性，这为BKCa通道对神经元活动的不同方面的影响奠定了基础。在这里，我们分析了BKCa通道对丘脑皮质中继神经元放电的贡献，并验证了BKCa通道活动影响CAE遗传性大鼠模型表型的假设。我们发现β(2)-肾上腺素能受体/蛋白激酶A通路的激活导致了BKCa通道的抑制。此外，BKCa通道影响爆发时激发的动作电位的数量，并在紧张性活动中产生尖峰频率适应。后一种结果得到了计算机模拟方法的证实。我们证明，BKCa通道的β(2)-肾上腺素能抑制阻止了峰频率适应，因此，可能显著支持丘脑皮质中继神经元的紧张性放电模式。此外，我们发现BKCa通道功能在癫痫WAG/RIJ中不同，因此可能有助于高度同步的癫痫网络活动。
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 (BKCa) under physiological conditions and in the pathophysiological state of CAE. The activation of BKCa 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 BKCa channels on different aspects of neuronal activity. Here, we analyse the contribution of BKCa channels to firing of thalamocortical relay neurons, and we test the hypothesis that BKCa channel activity affects the phenotype of a genetic rat model of CAE. We found that the activation of the beta(2)-adrenergic receptor/protein kinase A pathway resulted in BKCa channel inhibition. Furthermore, BKCa 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 beta(2)-adrenergic inhibition of BKCa channels prevents spike frequency adaptation and, thus, might significantly support the tonic firing mode of thalamocortical relay neurons. In addition, we show that BKCa channel functioning differs in epileptic WAG/Rij and thereby likely contributes to highly synchronised, epileptic network activity.