Department of Physiology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland.
Division of Biochemistry and Biotechnology, Department of Biosciences, University of Helsinki, P.O. Box 56, FIN-00014, Helsinki, Finland.
Sci Signal. 2018 Jan 16;11(513):eaan8784. doi: 10.1126/scisignal.aan8784.
Altered neuronal network formation and function involving dysregulated excitatory and inhibitory circuits are associated with fragile X syndrome (FXS). We examined functional maturation of the excitatory transmission system in FXS by investigating the response of FXS patient-derived neural progenitor cells to the glutamate analog (AMPA). Neural progenitors derived from induced pluripotent stem cell (iPSC) lines generated from boys with FXS had augmented intracellular Ca responses to AMPA and kainate that were mediated by Ca-permeable AMPA receptors (CP-AMPARs) lacking the GluA2 subunit. Together with the enhanced differentiation of glutamate-responsive cells, the proportion of CP-AMPAR and -methyl-d-aspartate (NMDA) receptor-coexpressing cells was increased in human FXS progenitors. Differentiation of cells lacking GluA2 was also increased and paralleled the increased inward rectification in neural progenitors derived from -knockout mice (the FXS mouse model). Human FXS progenitors had increased the expression of the precursor and mature forms of miR-181a, a microRNA that represses translation of the transcript encoding GluA2. Blocking GluA2-lacking, CP-AMPARs reduced the neurite length of human iPSC-derived control progenitors and further reduced the shortened length of neurites in human FXS progenitors, supporting the contribution of CP-AMPARs to the regulation of progenitor differentiation. Furthermore, we observed reduced expression of (the GluA2-encoding gene) in the frontal lobe of FXS mice, consistent with functional changes of AMPARs in FXS. Increased Ca influx through CP-AMPARs may increase the vulnerability and affect the differentiation and migration of distinct cell populations, which may interfere with normal circuit formation in FXS.
涉及兴奋性和抑制性回路失调的神经元网络形成和功能改变与脆性 X 综合征（FXS）有关。我们通过研究 FXS 患者来源的神经祖细胞对谷氨酸类似物（AMPA）的反应，检查兴奋性传递系统的功能成熟，以研究 FXS 患者来源的神经祖细胞对谷氨酸类似物（AMPA）的反应。从 FXS 男孩诱导多能干细胞 (iPSC) 系中衍生的神经祖细胞对 AMPA 和海人酸的细胞内 Ca 反应增强，这是由缺乏 GluA2 亚基的可通透 Ca2+的 AMPA 受体 (CP-AMPAR) 介导的。与谷氨酸反应细胞的分化增强一起，CP-AMPAR 和 -甲基-d-天冬氨酸 (NMDA) 受体共表达细胞的比例在人类 FXS 祖细胞中增加。缺乏 GluA2 的细胞分化也增加，与来自 - 敲除小鼠（FXS 小鼠模型）的神经祖细胞中增加的内向整流平行。人类 FXS 祖细胞增加了 miR-181a 的前体和成熟形式的表达，miR-181a 是一种抑制编码 GluA2 转录物翻译的 microRNA。阻断缺乏 GluA2 的 CP-AMPAR 减少了人 iPSC 衍生的对照祖细胞的神经突长度，并进一步减少了人 FXS 祖细胞缩短的神经突长度，支持 CP-AMPAR 对祖细胞分化的调节作用。此外，我们观察到 FXS 小鼠额叶中 （编码 GluA2 的基因）的表达减少，与 FXS 中 AMPAR 的功能变化一致。通过 CP-AMPAR 增加的 Ca2+内流可能会增加脆弱性并影响不同细胞群体的分化和迁移，这可能会干扰 FXS 中的正常回路形成。
