CaV3.1 is a tremor rhythm pacemaker in the inferior olive
CaV3.1 is a tremor rhythm pacemaker in the inferior olive
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DOI：
10.1073/pnas.1002995107
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发表时间：
2010-06-08
影响因子：
11.1
通讯作者：
Kim, Daesoo
中科院分区：
文献类型：
--
作者：
Park, Young-Gyun;Park, Hye-Yeon;Kim, Daesoo
由起搏神经元或脑中的回路进行的节律性运动通路激活已被提出作为运动协调的定时机制，并且该机制的异常增强可能导致病理性震颤。在这里，我们表明，增强的Ca（V）3.1 T型钙通道在下橄榄有助于发病的震颤在原发性震颤的药理学模型。在野生型小鼠中，给予harvestin后，从IO产生4- 10-Hz的同步神经元活动，然后传播到小脑运动回路，但在缺乏Ca（V）3.1基因的小鼠中不存在这些节律活动。脑干切片的细胞内记录显示，Ca（V）3.1缺陷的下橄榄神经元缺乏膜电位的阈下振荡，并且在存在干扰的情况下未能触发4- 10-Hz的节律性爆发放电。此外，通过shRNA选择性敲低下橄榄中的Ca（V）3.1基因有效地抑制了野生型小鼠中骆驼蓬碱诱导的震颤。根据膜片钳实验数据建立的数学模型表明，肝素可有效地增强Ca（V）3.1通道，通过改变超极化方向的电压依赖性反应。因此，Ca（V）3.1是下橄榄核神经元内在神经元振荡的分子起搏底物，这种机制的增强可以被认为是原发性震颤的病理原因。
The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of Ca(V)3.1 T-type Ca2+ channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking Ca(V)3.1 gene. Intracellular recordings in brain-stem slices revealed that the Ca(V)3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of Ca(V)3.1 gene in the inferior olive by shRNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate Ca(V)3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, Ca(V)3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor.