Uguagliati Beatrice, Grilli Mariagrazia
Laboratory of Neuroplasticity, Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy.
Cells. 2024 Dec 10;13(24):2037. doi: 10.3390/cells13242037.
Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. In the DS brain, since the prenatal life stages, the number of astrocytes is disproportional compared to the healthy brain. This increase is due to a shift from neuron to astrocyte differentiation during brain development. Astrocytes are involved in numerous functions during brain development, including balancing pro-neurogenic and pro-gliogenic stimuli, sustaining synapse formation, regulating excitatory/inhibitory signal equilibrium, and supporting the maintenance and integration of functional neural circuits. The enhanced number of astrocytes in the brain of DS individuals leads to detrimental consequences for brain development. This review summarizes the mechanisms underlying astrocytic dysfunction in DS, and particularly the dysregulation of key signaling pathways, which promote astrogliogenesis at the expense of neurogenesis. It further examines the implications of astrocytic alterations on dendritic branching, spinogenesis and synaptogenesis, and the impact of the abnormal astrocytic number in neural excitability and in the maintenance of the inhibitory/excitatory balance. Identifying deregulated pathways and the consequences of astrocytic alterations in early DS brain development may help in identifying new therapeutic targets, with the ultimate aim of ameliorating the cognitive disability that affects individuals with DS.
唐氏综合征（DS）的特征是严重的神经发育改变，最终导致DS的典型标志：智力残疾。在唐氏综合征患者的大脑中，自产前生命阶段起，星形胶质细胞的数量与健康大脑相比就不成比例。这种增加是由于大脑发育过程中神经元向星形胶质细胞分化的转变。星形胶质细胞在大脑发育过程中参与多种功能，包括平衡促神经发生和促神经胶质发生刺激、维持突触形成、调节兴奋性/抑制性信号平衡以及支持功能性神经回路的维持和整合。唐氏综合征患者大脑中星形胶质细胞数量的增加对大脑发育产生有害影响。本综述总结了唐氏综合征中星形胶质细胞功能障碍的潜在机制，特别是关键信号通路的失调，这些失调以神经发生为代价促进了星形胶质细胞生成。它进一步研究了星形胶质细胞改变对树突分支、棘突形成和突触发生的影响，以及星形胶质细胞数量异常对神经兴奋性和抑制性/兴奋性平衡维持的影响。确定唐氏综合征早期大脑发育中失调的通路以及星形胶质细胞改变的后果，可能有助于确定新的治疗靶点，最终目的是改善影响唐氏综合征患者的认知残疾。
