Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice.
Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice.
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DOI：
10.1038/ncomms14912
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发表时间：
2017-04-04
影响因子：
16.6
通讯作者：
Sillitoe RV
中科院分区：
文献类型：
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作者：
White JJ;Sillitoe RV
小脑功能的理论将下橄榄球与小脑的连接置于运动行为的中心。一个可能的含义是，橄榄小脑信号中断可能在启动运动疾病中发挥重要作用。为了测试这一点，我们设计了一种小鼠遗传学方法，仅在橄榄小脑突触处沉默多巴胺能信号。由此产生的小鼠具有严重的神经系统状况，其模仿在肌张力障碍（一种使人衰弱的运动疾病）中观察到的早发性扭曲、四肢僵硬和震颤。通过阻断橄榄小脑兴奋性神经传递，我们消除浦肯野细胞复合体尖峰，并诱导异常小脑核活动。药理学上抑制突变小鼠小脑核的不稳定输出改善了运动。此外，针对插入小脑核的深部脑刺激减少了这些小鼠的肌张力障碍样姿势。总的来说，我们的数据揭示了橄榄小脑功能障碍促进运动疾病表型的神经机制，并确定小脑核作为手术干预的治疗靶点。肌张力障碍被认为是由小脑信号传导障碍引起的。作者使用小鼠遗传方法沉默下橄榄至小脑通路中的兴奋性传递，导致动物出现肌张力障碍样体征，可使用DBS刺激该通路缓解。
Theories of cerebellar function place the inferior olive to cerebellum connection at the centre of motor behaviour. One possible implication of this is that disruption of olivocerebellar signalling could play a major role in initiating motor disease. To test this, we devised a mouse genetics approach to silence glutamatergic signalling only at olivocerebellar synapses. The resulting mice had a severe neurological condition that mimicked the early-onset twisting, stiff limbs and tremor that is observed in dystonia, a debilitating movement disease. By blocking olivocerebellar excitatory neurotransmission, we eliminated Purkinje cell complex spikes and induced aberrant cerebellar nuclear activity. Pharmacologically inhibiting the erratic output of the cerebellar nuclei in the mutant mice improved movement. Furthermore, deep brain stimulation directed to the interposed cerebellar nuclei reduced dystonia-like postures in these mice. Collectively, our data uncover a neural mechanism by which olivocerebellar dysfunction promotes motor disease phenotypes and identify the cerebellar nuclei as a therapeutic target for surgical intervention. Dystonia is thought to be driven by impairments in cerebellar signalling. The authors use a mouse genetic approach to silence excitatory transmission in the inferior olive to cerebellum pathway, resulting in dystonia-like signs in the animals which can be alleviated using DBS stimulation of the pathway.