Department of Basic Neuroscience, University of Geneva, 1211 Geneva, Switzerland.
Department of Basic Neuroscience, University of Geneva, 1211 Geneva, Switzerland
eNeuro. 2020 Apr 7;7(2). doi: 10.1523/ENEURO.0297-19.2020. Print 2020 Mar/Apr.
Huntington's disease (HD) is a neurodegenerative disease notably characterized by progressive motor symptoms. Although the loss of medium spiny neurons (MSNs) in the striatum has been associated with motor deficits, premanifest patients already present cognitive deficiencies and show early signs of motor disabilities. Here, in a YAC128 HD mouse model, we identified impairment in motor skill consolidation at the age of 11-14 weeks. Using optogenetic stimulation, we found that excitatory synaptic transmission from motor cortex to MSNs located in the dorsolateral part of the striatum (DLS) is altered. Using single pellet reaching task, we observed that while motor skill consolidation is accompanied by a dynamic change in AMPA/NMDA ratio in wild-type (WT) mice, this form of synaptic plasticity does not occur in YAC128 mice. This study not only proposes new meaningful insight in the synaptopathic mechanisms of HD, but also highlights that deficit in motor skill consolidation-dependent synaptic plasticity at motor cortex to DLS synapses represents an early biomarker for HD.
亨廷顿病（HD）是一种神经退行性疾病，其特征主要为进行性运动症状。尽管纹状体中的中型棘突神经元（MSNs）的丧失与运动缺陷有关，但在有明显症状前的患者中已经存在认知缺陷，并出现运动功能障碍的早期迹象。在这里，在 YAC128HD 小鼠模型中，我们在 11-14 周龄时发现运动技能巩固受损。使用光遗传学刺激，我们发现来自运动皮层到纹状体背外侧部分（DLS）的 MSNs 的兴奋性突触传递发生改变。使用单个颗粒到达任务，我们观察到，虽然运动技能巩固伴随着 WT 小鼠中 AMPA/NMDA 比率的动态变化，但 YAC128 小鼠中不会发生这种形式的突触可塑性。这项研究不仅为 HD 的突触病机制提出了新的有意义的见解，还强调了运动皮层到 DLS 突触的运动技能巩固依赖性突触可塑性缺陷代表了 HD 的早期生物标志物。
