State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
Stem Cell Reports. 2018 Apr 10;10(4):1251-1266. doi: 10.1016/j.stemcr.2018.02.001. Epub 2018 Mar 8.
The brain of Down syndrome (DS) patients exhibits fewer interneurons in the cerebral cortex, but its underlying mechanism remains unknown. By morphometric analysis of cortical interneurons generated from DS and euploid induced pluripotent stem cells (iPSCs), we found that DS GABA neurons are smaller and with fewer neuronal processes. The proportion of calretinin over calbindin GABA neurons is reduced, and the neuronal migration capacity is decreased. Such phenotypes were replicated following transplantation of the DS GABAergic progenitors into the mouse medial septum. Gene expression profiling revealed altered cell migratory pathways, and correction of the PAK1 pathway mitigated the cell migration deficit in vitro. These results suggest that impaired migration of DS GABAergic neurons may contribute to the reduced number of interneurons in the cerebral cortex and hippocampus in DS patients.
唐氏综合征（DS）患者的大脑皮层中少突胶质细胞，但其中的潜在机制尚不清楚。通过对来自 DS 和整倍体诱导多能干细胞（iPSC）的皮层中间神经元的形态计量学分析，我们发现 DS GABA 神经元更小，且神经元突起更少。钙结合蛋白 1（calbindin）阳性 GABA 神经元的比例减少，神经元迁移能力降低。将 DS GABA 能祖细胞移植到小鼠的内侧隔核后，可复制上述表型。基因表达谱分析显示，细胞迁移途径发生改变，纠正 PAK1 途径可减轻体外细胞迁移缺陷。这些结果表明，DS GABA 能神经元迁移受损可能导致 DS 患者大脑皮层和海马区中间神经元数量减少。
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