Table_1_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，其病理特征为上下运动神经元同时变性。尽管历经数十年研究，目前学界仍未找到治愈该病的手段或疾病修饰治疗方案，这凸显了深化对疾病发病机制与细胞类型易感性认知的迫切需求。神经元兴奋性异常是ALS患者及该病动物模型中均被广泛报道的常见现象，但目前学界对其涉及的细胞与环路机制，以及上述观察结果与分子改变、最终细胞死亡之间的因果关联仍知之甚少。本文综述了来自临床研究、细胞特异性电生理研究、动物模型中的基因操作与分子表征实验，以及体外培养实验的相关证据，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、功能及连接发生的复杂改变，与ALS的发病存在因果关联。此外，本文还总结了当前关于星形胶质细胞（astrocyte）有害作用的研究进展，并针对神经元兴奋性异常的相关机制，重新评估了学界常提出的谷氨酸介导的兴奋性中毒假说。综合上述研究结果，神经元兴奋-抑制平衡的多维度、细胞类型特异性、脑区特异性及疾病分期特异性紊乱，是ALS病理生理学的核心特征之一。