Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, 08036, Barcelona, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.
BMC Biol. 2020 May 28;18(1):58. doi: 10.1186/s12915-020-00794-4.
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. GABA 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.
神经退行性疾病的网络改变通常先于症状和功能缺陷出现。因此，早期识别对于改善预后至关重要。在亨廷顿病（HD）中，涉及运动功能处理的皮质纹状体网络是最受影响的神经基础。然而，网络改变是纹状体还是皮层的内在特征尚不完全清楚。
为了确定早期 HD 的神经缺陷，我们对 HD 纹状体和皮层培养物中的神经元集合钙活动和网络拓扑进行了表征。我们使用了大规模钙成像技术，并结合基于活动的网络推断分析。我们提取了集体活动事件，并推断了来自野生型和 R6/1 亨廷顿病小鼠模型的皮层和纹状体原代培养物中的神经元网络拓扑。纹状体，但不是皮层，HD 网络显示出较低的活动和减弱的信息整合能力。在健康和 HD 纹状体培养物中阻断 GABA 受体产生了类似的协调集合活动和网络拓扑，这突出表明 HD 中的纹状体系统的兴奋性成分得以保留。相反，NMDA 受体的激活增加了单个神经元的活动，而协调活动变得高度可变且不明确。有趣的是，通过增强 NMDA 活性，我们纠正了纹状体 HD 网络改变。
总的来说，我们的综合方法强调了纹状体网络整合能力缺陷是 HD 基底节功能障碍的主要原因，并表明增加兴奋性驱动可能是一种潜在的干预措施。此外，我们的工作为评估基底节疾病治疗干预后的体外网络恢复提供了有价值的工具。
