Role of cerebellar GABAergic dysfunctions in the origins of essential tremor
Role of cerebellar GABAergic dysfunctions in the origins of essential tremor
复制标题
小脑 GABA 能功能障碍在特发性震颤起源中的作用
DOI：
10.1073/pnas.1817689116
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Santaniello, Sabato
中科院分区：
文献类型：
--
作者：
Zhang, Xu;Santaniello, Sabato
特发性震颤（ET）是最常见的运动障碍之一，但其起源是难以捉摸的。由于下橄榄核神经元的起搏特性，下橄榄核（ION）被假设为震颤的主要发生器，但在ET下ION的结构和功能变化是不可能的。相反，在小脑-丘脑-皮质网络中报告了功能障碍，包括从小脑皮质到齿状核的GABA能投射功能障碍。然而，震颤与小脑连接功能障碍之间的关系仍不清楚。为了解决这个问题，我们建立了一个计算模型的皮质-小脑-丘脑-皮质回路。我们模拟了齿状核GABAAα1受体亚单位的进行性丢失和α2/3受体亚单位的上调的影响，并相应地研究了放电模式沿着环路的演变。该模型紧密地再现了环中每个结构的实验证据。它表明，改变到齿状核的GABA能电流的幅度和衰减时间可以促进整个网络中震颤频率的持续振荡活动以及丘脑中的强烈爆发活动，这与ET患者中丘脑震颤细胞的观察结果一致。震颤相关的振荡开始于小的神经群体，并随着突触功能障碍的增加而扩散到更大的网络，而丘脑高频刺激抑制了丘脑中的震颤相关活动，但增加了橄榄小脑回路中的振荡频率。这些结果提示了小脑功能障碍下震颤产生的机制，这可能解释了ET的起源。
Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive. The inferior olivary nucleus (ION) has been hypothesized as the prime generator of tremor because of the pacemaker properties of ION neurons, but structural and functional changes in ION are unlikely under ET. Abnormalities have instead been reported in the cerebello-thalamo-cortical network, including dysfunctions of the GABAergic projections from the cerebellar cortex to the dentate nucleus. It remains unclear, though, how tremor would relate to a dysfunction of cerebellar connectivity. To address this question, we built a computational model of the cortico-cerebello-thalamo-cortical loop. We simulated the effects of a progressive loss of GABAAα1-receptor subunits and up-regulation of α2/3-receptor subunits in the dentate nucleus, and correspondingly, we studied the evolution of the firing patterns along the loop. The model closely reproduced experimental evidence for each structure in the loop. It showed that an alteration of amplitudes and decay times of the GABAergic currents to the dentate nucleus can facilitate sustained oscillatory activity at tremor frequency throughout the network as well as a robust bursting activity in the thalamus, which is consistent with observations of thalamic tremor cells in ET patients. Tremor-related oscillations initiated in small neural populations and spread to a larger network as the synaptic dysfunction increased, while thalamic high-frequency stimulation suppressed tremor-related activity in thalamus but increased the oscillation frequency in the olivocerebellar loop. These results suggest a mechanism for tremor generation under cerebellar dysfunction, which may explain the origin of ET.
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