Kanyshkova Tatyana, Ehling Petra, Cerina Manuela, Meuth Patrick, Zobeiri Mehrnoush, Meuth Sven G, Pape Hans-Christian, Budde Thomas
Institut für Physiologie I, Robert-Koch-Str. 27a, D-48149 Münster, Germany.
Institut für Physiologie I, Robert-Koch-Str. 27a, D-48149 Münster, Germany; Department für Neurologie, Klinik für Allgemeine Neurologie and Institut für Physiologie, Abteilung für Neuropathophysiologie, Albert-Schweitzer-Campus 1, Westfälische Wilhelms-Universität, D-48149 Münster, Germany.
Mol Cell Neurosci. 2014 Jul;61:110-22. doi: 10.1016/j.mcn.2014.06.005. Epub 2014 Jun 7.
The polygenic origin of generalized absence epilepsy results in dysfunction of ion channels that allows the switch from physiological asynchronous to pathophysiological highly synchronous network activity. Evidence from rat and mouse models of absence epilepsy indicates that altered Ca(2+) channel activity contributes to cellular and network alterations that lead to seizure activity. Under physiological circumstances, high voltage-activated (HVA) Ca(2+) channels are important in determining the thalamic firing profile. Here, we investigated a possible contribution of HVA channels to the epileptic phenotype using a rodent genetic model of absence epilepsy. In this study, HVA Ca(2+) currents were recorded from neurons of three different thalamic nuclei that are involved in both sensory signal transmission and rhythmic-synchronized activity during epileptic spike-and-wave discharges (SWD), namely the dorsal part of the lateral geniculate nucleus (dLGN), the ventrobasal thalamic complex (VB) and the reticular thalamic nucleus (NRT) of epileptic Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) and non-epileptic August Copenhagen Irish (ACI) rats. HVA Ca(2+) current densities in dLGN neurons were significantly increased in epileptic rats compared with non-epileptic controls while other thalamic regions revealed no differences between the strains. Application of specific channel blockers revealed that the increased current was carried by L-type Ca(2+) channels. Electrophysiological evidence of increased L-type current correlated with up-regulated mRNA and protein expression of a particular L-type channel, namely Cav1.3, in dLGN of epileptic rats. No significant changes were found for other HVA Ca(2+) channels. Moreover, pharmacological inactivation of L-type Ca(2+) channels results in altered firing profiles of thalamocortical relay (TC) neurons from non-epileptic rather than from epileptic rats. While HVA Ca(2+) channels influence tonic and burst firing in ACI and WAG/Rij differently, it is discussed that increased Cav1.3 expression may indirectly contribute to increased robustness of burst firing and thereby the epileptic phenotype of absence epilepsy.
全面性失神癫痫的多基因起源导致离子通道功能障碍，使得生理上的异步网络活动转变为病理生理上的高度同步网络活动。来自失神癫痫大鼠和小鼠模型的证据表明，钙通道活性改变促成了导致癫痫发作活动的细胞和网络改变。在生理情况下，高电压激活（HVA）钙通道在决定丘脑放电模式方面很重要。在此，我们使用失神癫痫的啮齿动物遗传模型研究了HVA通道对癫痫表型的可能作用。在本研究中，从参与癫痫棘波和慢波放电（SWD）期间感觉信号传递和节律同步活动的三个不同丘脑核的神经元记录HVA钙电流，即来自荷兰莱顿的癫痫性Wistar白化Glaxo大鼠（WAG/Rij）和非癫痫性奥胡斯哥本哈根爱尔兰大鼠（ACI）的外侧膝状体核背侧部分（dLGN）、腹侧基底丘脑复合体（VB）和丘脑网状核（NRT）。与非癫痫对照相比，癫痫大鼠dLGN神经元中的HVA钙电流密度显著增加，而其他丘脑区域在不同品系之间未显示差异。应用特异性通道阻滞剂表明，增加的电流由L型钙通道携带。L型电流增加的电生理证据与癫痫大鼠dLGN中特定L型通道即Cav1.3的mRNA和蛋白表达上调相关。其他HVA钙通道未发现显著变化。此外，L型钙通道的药理学失活导致非癫痫大鼠而非癫痫大鼠丘脑皮质中继（TC）神经元的放电模式改变。虽然HVA钙通道对ACI和WAG/Rij的紧张性和爆发性放电影响不同，但有人认为Cav1.3表达增加可能间接导致爆发性放电的稳健性增加，从而导致失神癫痫的癫痫表型。
