Table_3_Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology.pdf

Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the degeneration of both upper and lower motor neurons. Despite decades of research, we still to date lack a cure or disease modifying treatment, emphasizing the need for a much-improved insight into disease mechanisms and cell type vulnerability. Altered neuronal excitability is a common phenomenon reported in ALS patients, as well as in animal models of the disease, but the cellular and circuit processes involved, as well as the causal relevance of those observations to molecular alterations and final cell death, remain poorly understood. Here, we review evidence from clinical studies, cell type-specific electrophysiology, genetic manipulations and molecular characterizations in animal models and culture experiments, which argue for a causal involvement of complex alterations of structure, function and connectivity of different neuronal subtypes within the cortical and spinal cord motor circuitries. We also summarize the current knowledge regarding the detrimental role of astrocytes and reassess the frequently proposed hypothesis of glutamate-mediated excitotoxicity with respect to changes in neuronal excitability. Together, these findings suggest multifaceted cell type-, brain area- and disease stage- specific disturbances of the excitation/inhibition balance as a cardinal aspect of ALS pathophysiology.

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis, ALS）是一种致命性疾病，以上下运动神经元同时变性为典型特征。尽管历经数十年研究，学界至今仍未找到治愈该疾病的方法或可延缓疾病进展的疾病修饰治疗手段，这凸显出深入解析疾病发病机制与细胞类型易感性的迫切需求。神经元兴奋性异常是ALS患者及该疾病动物模型中均被广泛报道的常见现象，但相关的细胞与环路机制，以及此类观察结果与分子改变、最终细胞死亡之间的因果关联，仍未得到充分阐明。本综述梳理了来自临床研究、细胞类型特异性电生理（cell type-specific electrophysiology）、动物模型与体外培养实验中的基因操作及分子表征相关证据，这些证据表明大脑皮层与脊髓运动环路内不同神经元亚型的结构、功能及连接的复杂异常，在ALS发病中存在因果性参与。我们还总结了当前学界关于星形胶质细胞（astrocytes）的有害作用的认知，并针对神经元兴奋性改变相关的谷氨酸（glutamate）介导兴奋性毒性这一常被提出的假说进行了重新评估。综上，上述研究结果提示，多维度的细胞类型、脑区及疾病分期特异性的兴奋-抑制平衡紊乱，是ALS病理生理学的核心特征之一。