Deletion of phospholipase C β4 in thalamocortical relay nucleus leads to absence seizures
Deletion of phospholipase C β4 in thalamocortical relay nucleus leads to absence seizures
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DOI：
10.1073/pnas.0912204106
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发表时间：
2009-12-22
影响因子：
11.1
通讯作者：
Shin, Hee-Sup
中科院分区：
文献类型：
--
作者：
Cheong, Eunji;Zheng, Yihong;Shin, Hee-Sup
在脑电图上，癫痫的特征是皮层尖波放电（SWDs），通常伴随着丘脑皮质（TC）神经元在t型Ca2+电流驱动下从强直放电到爆发放电的转变。我们最近发现，磷脂酶C β 4 （PLC β 4）通路通过同时调节t型和l型Ca2+电流来调节TC神经元的放电模式，这促使我们研究TC放电模式对失神癫痫的贡献。在膜电位轻微超极化后，PLC β 4缺陷的TC神经元很容易转变为振荡的突发放电模式。tc有限敲除和全动物敲除PLC β 4可诱导自发性SWDs，同时伴有行为骤停，并增加对药物性SWDs的易感性，表明丘脑PLC β 4的缺失可导致失神发作的发生。丘脑输注t型而非l型Ca2+通道阻滞剂可有效抑制SWDs。这些结果揭示了TC神经元在失神发作发生中的主要作用，并提供了强有力的证据，证明TC神经元放电特性的改变足以产生失神发作。我们的研究提出了PLC β 4缺陷小鼠作为失神癫痫的潜在动物模型。
Absence seizures are characterized by cortical spike-wave discharges (SWDs) on electroencephalography, often accompanied by a shift in the firing pattern of thalamocortical (TC) neurons from tonic to burst firing driven by T-type Ca2+ currents. We recently demonstrated that the phospholipase C beta 4 (PLC beta 4) pathway tunes the firing mode of TC neurons via the simultaneous regulation of T-and L-type Ca2+ currents, which prompted us to investigate the contribution of TC firing modes to absence seizures. PLC beta 4-deficient TC neurons were readily shifted to the oscillatory burst firing mode after a slight hyperpolarization of membrane potential. TC-limited knockdown as well as whole-animal knockout of PLC beta 4 induced spontaneous SWDs with simultaneous behavioral arrests and increased the susceptibility to drug-induced SWDs, indicating that the deletion of thalamic PLC beta 4 leads to the genesis of absence seizures. The SWDs were effectively suppressed by thalamic infusion of a T-type, but not an L-type, Ca2+ channel blocker. These results reveal a primary role of TC neurons in the genesis of absence seizures and provide strong evidence that an alteration of the firing property of TC neurons is sufficient to generate absence seizures. Our study presents PLC beta 4-deficient mice as a potential animal model for absence seizures.