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The role of astrocytes in Fragile X neurobiology.

机译:星形胶质细胞在脆性X神经生物学中的作用。

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摘要

Fragile X Syndrome (FXS) is the most common inherited disease of mental impairment, typically caused by a mutation in the Fragile X mental retardation 1 (FMR1) gene. The clinical features are thought to result from abnormal neurobiology due to a lack of the Fragile X mental retardation protein (FMRP). Previously, it was thought that FMRP was confined exclusively to neurons; however, our laboratory recently discovered that astrocytes also express FMRP. Consequently, it is possible that astrocytes also suffer abnormalities as a result of a lack of FMRP. Astrocytes play integral roles in the development and maintenance of communication in the central nervous system. Therefore, it is now important to determine the contribution of astrocytes to the abnormal neuronal phenotype seen in FXS. In these experiments, neurons and astrocytes were independently isolated from wild type (WT) or FMR1 null mice and grown in a co-culture. Neurons were evaluated using immunocytochemistry in combination with computer-aided morphometric and synaptic protein analyses. The findings presented here provide convincing evidence that Fragile X astrocytes contribute to the abnormal neurobiology seen in FXS. Fragile X astrocytes alter the dendrite morphology and excitatory synaptic protein expression of WT neurons in culture; and, importantly, when Fragile X neurons are grown with WT astrocytes these changes are prevented. Interestingly, the Fragile X astrocytes appear to act by causing a delay in development; even WT neurons grown in the presence of Fragile X astrocytes, that displayed an abnormal phenotype at 7 days in culture, exhibited nearly normal dendrite morphology and expression of excitatory synapses at 21 days. Furthermore, the results suggest that the dendritic abnormalities induced by the Fragile X astrocytes specifically target neurons with a spiny stellate morphology. This research establishes a role for astrocytes in the development of the abnormal neurobiology seen in FXS, and as such, the results presented here have significant implications for Fragile X research. The novel prospect that astrocytes are key contributing components in the development of FXS provides an exciting new direction for investigations into the mechanisms underlying FXS, with many unexplored avenues for potential treatment strategies.
机译:脆弱X综合征(FXS)是最常见的精神障碍遗传疾病,通常是由脆弱X智力低下1(FMR1)基因突变引起的。临床特征被认为是由于缺乏脆性X智力低下蛋白(FMRP)而导致的神经生物学异常所致。以前,人们认为FMRP仅限于神经元。但是,我们的实验室最近发现星形胶质细胞也表达FMRP。因此,由于缺乏FMRP,星形胶质细胞也可能遭受异常。星形胶质细胞在中枢神经系统通讯的发展和维持中起着不可或缺的作用。因此,现在重要的是确定星形胶质细胞对在FXS中看到的异常神经元表型的贡献。在这些实验中,神经元和星形胶质细胞分别从野生型(WT)或FMR1 null小鼠中分离出来,并在共培养物中生长。使用免疫细胞化学结合计算机辅助形态计量和突触蛋白分析来评估神经元。此处提出的发现提供了令人信服的证据,表明脆弱的X星形胶质细胞促成了FXS中所见的异常神经生物学。易碎的X星形胶质细胞改变了WT神经元在培养物中的树突形态和兴奋性突触蛋白表达。而且,重要的是,当脆弱的X神经元与野生型星形胶质细胞一起生长时,可以防止这些变化。有趣的是,易碎的X星形胶质细胞似乎通过引起发育延迟而起作用。即使在存在脆弱的X星形胶质细胞的情况下生长的WT神经元,在培养7天时表现出异常的表型,在21天时仍表现出接近正常的树突形态和兴奋性突触的表达。此外,结果表明,由脆弱X星形胶质细胞诱导的树突状异常特异地靶向具有棘状星状形态的神经元。这项研究确立了星形胶质细胞在FXS中发现的异常神经生物学发展中的作用,因此,此处给出的结果对脆弱X的研究具有重要意义。星形胶质细胞是FXS发展中关键的组成部分的新颖前景为研究FXS的潜在机制提供了令人振奋的新方向,并为潜在的治疗策略提供了许多未探索的途径。

著录项

  • 作者

    Jacobs, Shelley.;

  • 作者单位

    McMaster University (Canada).;

  • 授予单位 McMaster University (Canada).;
  • 学科 Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 326 p.
  • 总页数 326
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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