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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Partial Reversal Of Rett Syndrome-like Symptoms In Mecp2 Mutant Mice
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Partial Reversal Of Rett Syndrome-like Symptoms In Mecp2 Mutant Mice

机译：Mecp2突变小鼠的Rett综合征样症状的部分逆转。

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摘要

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.
机译：Rett综合征（RTT）是X连锁智力低下的一种严重形式，由编码甲基CpG结合蛋白2（MECP2）的基因突变引起。缺乏MeCP2的小鼠具有一系列模仿人类综合征的生理和神经异常。在这里，我们显示用胰岛素样生长因子1（IGF-1）的活性肽片段对MeCP2突变型小鼠进行全身治疗可延长小鼠的寿命，改善运动功能，改善呼吸模式并减少心率不规则。另外，用IGF-1肽治疗增加了突变小鼠的脑重量。多种测量结果支持RTT由大脑中突触成熟不足引起的假说：MeCP2突变小鼠的树突棘稀疏，运动皮质锥体神经元的PSD-95降低，同一神经元的突触振幅降低，体内皮质可塑性持久。使用IGF-1肽治疗可部分恢复脊柱密度和突触幅度，增加PSD-95，并使皮质可塑性稳定至野生型水平。因此，我们的结果有力地表明，IGF-1可作为RTT药物治疗的候选药物，并可能治疗因突触成熟延迟而引起的其他CNS疾病。

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  • 作者

    Daniela Tropea; Emanuela Giacometti; Nathan R. Wilson; Caroline Beard; Cortina McCurry; Dong Dong Fu; Ruth Flannery; Rudolf Jaenisch; Mriganka Sur;

  • 作者单位

    Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Whitehead Institute for Biomedical Research, Cambridge, MA 02142;

    Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Whitehead Institute for Biomedical Research, Cambridge, MA 02142;

    Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Whitehead Institute for Biomedical Research, Cambridge, MA 02142;

    Whitehead Institute for Biomedical Research, Cambridge, MA 02142;

    Whitehead Institute for Biomedical Research, Cambridge, MA 02142 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    igf-1; plasticity; autism; BRAIN; synapse;

    机译：igf-1;可塑性;自闭症;脑;突触;

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