Network alterations underlying neurodegenerative diseases often precede symptoms and functional deficits. Thus, their early identification is central for improved prognosis. In Huntington’s disease (HD), the cortico-striatal networks, involved in motor function processing, are the most compromised neural substrate. However, whether the network alterations are intrinsic of the striatum or the cortex is not fully understood. In order to identify early HD neural deficits, we characterized neuronal ensemble calcium activity and network topology of HD striatal and cortical cultures. We used large-scale calcium imaging combined with activity-based network inference analysis. We extracted collective activity events and inferred the topology of the neuronal network in cortical and striatal primary cultures from wild-type and R6/1 mouse model of HD. Striatal, but not cortical, HD networks displayed lower activity and a lessened ability to integrate information. GABAA receptor blockade in healthy and HD striatal cultures generated similar coordinated ensemble activity and network topology, highlighting that the excitatory component of striatal system is spared in HD. Conversely, NMDA receptor activation increased individual neuronal activity while coordinated activity became highly variable and undefined. Interestingly, by boosting NMDA activity, we rectified striatal HD network alterations. Overall, our integrative approach highlights striatal defective network integration capacity as a major contributor of basal ganglia dysfunction in HD and suggests that increased excitatory drive may serve as a potential intervention. In addition, our work provides a valuable tool to evaluate in vitro network recovery after treatment intervention in basal ganglia disorders.

中文翻译：

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协调神经元活动和网络拓扑结构的缺陷是亨廷顿舞蹈病的纹状体标志。

导致神经退行性疾病的网络变化通常先于症状和功能缺陷。因此，它们的早期识别对于改善预后至关重要。在亨廷顿舞蹈病（HD）中，参与运动功能处理的皮质-纹状体网络是受损最严重的神经基质。但是，网络变化是纹状体还是皮层固有的，尚未完全了解。为了识别早期的高清神经缺陷，我们对高清纹状体和皮质培养物的神经元合钙活性和网络拓扑结构进行了表征。我们将大型钙成像与基于活动的网络推理分析相结合。我们从HD的野生型和R6 / 1小鼠模型中提取了集体活动事件，并推断了皮层和纹状体原代培养物中神经元网络的拓扑。纹状体而非皮质的高清网络显示出较低的活动性，并且整合信息的能力减弱。在健康和HD纹状体文化中，GABAA受体阻滞产生相似的协调整体活动和网络拓扑结构，这表明HD中不存在纹状体系统的兴奋性成分。相反，NMDA受体激活增加了个体神经元活动，而协调活动变得高度可变且不确定。有趣的是，通过增强NMDA活性，我们纠正了纹状高清网络的改变。总体而言，我们的综合方法强调了纹状体缺陷网络整合能力是HD基底神经节功能障碍的主要因素，并表明增加的兴奋性驱动可能是一种潜在的干预措施。此外，