Functional stabilization of weakened thalamic pacemaker channel regulation in rat absence epilepsy
Functional stabilization of weakened thalamic pacemaker channel regulation in rat absence epilepsy
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DOI：
10.1113/jphysiol.2006.110486
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发表时间：
2006-08-15
影响因子：
5.5
通讯作者：
Luthi, Anita
中科院分区：
文献类型：
--
作者：
Kuisle, Mira;Wanaverbecq, Nicolas;Luthi, Anita
超极化激活的阳离子非选择性（HCN）通道携带的起搏电流（I-h）的异常功能影响神经元的兴奋性并伴随癫痫，但其在癫痫发生和慢性癫痫中的独特作用尚不清楚。我们探讨了I-H功能和亚基组成在前和慢性癫痫阶段的丘脑皮质（TC）神经元的遗传缺失癫痫大鼠斯特拉斯堡（GAERS）。在成熟的体感TC细胞，在体内和体外的I-h的电压门控是不变的。然而，增强I-h的相位，近生理，cAMP脉冲减少了类似的40%和半最大cAMP浓度增加了类似的5倍。在GAERS中，I-h对其主要细胞调节剂的反应性降低先于癫痫发作，在整个慢性状态下持续存在，并伴有cAMP不敏感的HCN 1通道mRNA表达增强（> 50%），而HCN 2和HCN 4的mRNA水平无变化。为了评估TC细胞兴奋性的改变，我们监测了由Ca 2+触发的cAMP合成诱导的I-H的缓慢上调，这对于终止体外同步振荡非常重要。值得注意的是，反复反弹Ca 2+尖峰诱发正常的缓慢I-H的上调成熟的GAERS神经元，足以减弱自发性节律性爆发放电。这些适应性机制发生在cAMP周转的上游，并涉及在重复低阈值Ca 2+放电后增强的细胞内Ca 2+积累。因此，HCN通道似乎在癫痫中发挥双重作用。减弱cAMP结合HCN通道之前，并可能促进，癫痫发生在GAERS，而补偿机制稳定I-H功能有助于终止的尖峰和波放电在慢性癫痫。
Aberrant function of pacemaker currents (I-h), 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 I-h 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 I-h was unaltered in mature somatosensory TC cells, both in vivo and in vitro. However, the enhancement of I-h by phasic, near-physiological, cAMP pulses was diminished by similar to 40% and the half-maximal cAMP concentration increased by similar to 5-fold. This decreased responsiveness of I-h 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 I-h that is induced by Ca2+-triggered cAMP synthesis and important for terminating in vitro synchronized oscillations. Remarkably, repetitive rebound Ca2+ spikes evoked normal slow I-h 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 I-h function contribute to the termination of spike-and-wave discharges in chronic epilepsy.