Fernández-Blanco Álvaro, González-Arias Candela, Sierra Cesar, Zamora-Moratalla Alfonsa, Perea Gertrudis, Dierssen Mara
Center for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 08003 Barcelona, Spain.
Department of Functional and Systems Neurobiology, Cajal Institute, CSIC, 28006 Madrid, Spain.
Cells. 2025 Aug 28;14(17):1332. doi: 10.3390/cells14171332.
Brain pathophysiology in Down syndrome (DS), the most common genetic cause of intellectual disability, has traditionally been considered a consequence of neuronal dysfunction. However, although it is well documented that astrocytes play a critical role in brain homeostasis, synaptic regulation, and neuronal support, and their malfunction has been associated with the onset and progression of different neurological disorders, only a few studies have addressed whether astrocyte dysfunction can contribute to the DS pathophysiology. Astrocytes are increased in number and size, and show increased levels of expression of astroglial markers like S100β and GFAP. In this study, we detected a region-specific increase in astrocyte population in CA1 and, to a lesser extent, in the dentate gyrus. Single-nucleus transcriptomic profiling identified markers associated with reactive astroglia, synaptic transmission, and neuroinflammation in trisomic astrocytes. Functional analysis revealed abnormal Ca oscillations in trisomic astrocytes and impaired astrocyte-to-neuron communication in CA1, the most affected subregion, leading to astrocyte-mediated excitatory synaptic depression. Our findings demonstrate that astrocytes play an active and critical role in the pathophysiology of DS, not only as reactive responders to neuronal injury but as key contributors to the disease process itself. This astrocytic dysfunction presents a region-specific distribution within the hippocampus, suggesting localized vulnerability and complex glial involvement in DS-related neuropathology.
唐氏综合征（DS）是智力残疾最常见的遗传病因，其大脑病理生理学传统上被认为是神经元功能障碍的结果。然而，尽管有充分的文献记载星形胶质细胞在脑内稳态、突触调节和神经元支持中起关键作用，且其功能异常与不同神经疾病的发生和进展有关，但只有少数研究探讨了星形胶质细胞功能障碍是否会导致DS的病理生理学变化。星形胶质细胞的数量和大小增加，且显示出星形胶质细胞标志物如S100β和GFAP的表达水平升高。在本研究中，我们检测到CA1区星形胶质细胞数量有区域特异性增加，齿状回的增加程度较小。单核转录组分析确定了与三体性星形胶质细胞中反应性星形胶质细胞、突触传递和神经炎症相关的标志物。功能分析显示三体性星形胶质细胞中钙振荡异常，且在受影响最严重的亚区域CA1中星形胶质细胞与神经元之间的通讯受损，导致星形胶质细胞介导的兴奋性突触抑制。我们的研究结果表明，星形胶质细胞在DS的病理生理学中起积极且关键的作用，不仅是对神经元损伤的反应性应答者，也是疾病进程本身的关键促成因素。这种星形胶质细胞功能障碍在海马体内呈现区域特异性分布，提示DS相关神经病理学中存在局部易损性和复杂的胶质细胞参与。
