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首页> 外文期刊>The Cerebellum >High Transgene Expression by Lentiviral Vectors Causes Maldevelopment of Purkinje Cells In Vivo
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High Transgene Expression by Lentiviral Vectors Causes Maldevelopment of Purkinje Cells In Vivo

机译：慢病毒载体的高转基因表达导致浦肯野细胞体内发育不良

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摘要

Lentiviral vectors are promising as gene-transfer vehicles for gene therapy targeted to intractable brain diseases. Although lentiviral vectors are thought to exert little toxicity on infected cells, the adverse influence of viral infection on vulnerable developing neurons has not been well studied. Here, we examined whether lentiviral vector infection and subsequent transgene expression affected the morphological and functional maturation of vigorously developing cerebellar Purkinje cells in vivo. Lentiviral vectors expressing GFP under the control of the murine stem cell virus (MSCV) promoter were injected into the cerebellar cortex of neonatal rat pups. Three weeks after treatment, GFP-expressing Purkinje cells were compared with control Purkinje cells from phosphate-buffered saline-injected rats. Analysis of the dendritic tree showed that total dendrite length in GFP-expressing Purkinje cells was almost 80% that in control Purkinje cells. Electrophysiological examination showed that short-term synaptic plasticity at parallel fiber–Purkinje cell synapses and climbing fiber–Purkinje cell synapses was significantly altered in GFP-expressing Purkinje cells. In contrast, maldevelopment of infected Purkinje cells was substantially attenuated when lentiviral vectors with much weaker promoter activity were used. These results suggest that the maldevelopment of Purkinje cells was mainly caused by subsequent expression of a high amount of GFP driven by the strong MSCV promoter. Thus, the use of lentiviral vectors carrying a strong promoter may require particular precautions when applying them to neurological disorders of infants.
机译：慢病毒载体有望作为针对难治性脑疾病的基因治疗的基因转移载体。尽管认为慢病毒载体对感染的细胞几乎没有毒性，但尚未充分研究病毒感染对脆弱的发育中神经元的不利影响。在这里，我们检查了慢病毒载体感染和随后的转基因表达是否影响体内发育旺盛的小脑浦肯野细胞的形态和功能成熟。将在鼠干细胞病毒（MSCV）启动子控制下表达GFP的慢病毒载体注入新生大鼠幼崽的小脑皮质。处理三周后，将表达GFP的浦肯野细胞与来自磷酸盐缓冲液注射盐水的大鼠的对照浦肯野细胞进行比较。对树状树的分析表明，表达GFP的Purkinje细胞中的总树突长度几乎是对照Purkinje细胞中的总树突长度的80％。电生理检查显示，在表达GFP的浦肯野细胞中，平行纤维-浦肯野细胞突触和攀爬纤维-浦肯野细胞突触的短期突触可塑性显着改变。相反，当使用具有弱得多的启动子活性的慢病毒载体时，被感染的浦肯野细胞的发育不良被大大减弱。这些结果表明浦肯野细胞的发育不良主要是由强MSCV启动子驱动的大量GFP的后续表达引起的。因此，当将带有强启动子的慢病毒载体用于婴儿的神经系统疾病时，可能需要采取特殊的预防措施。

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  • 来源
    《The Cerebellum》 |2010年第3期|291-302|共12页
  • 作者

    Yusuke Sawada; Go Kajiwara; Akira Iizuka; Kiyohiko Takayama; Anton N. Shuvaev; Chiho Koyama; Hirokazu Hirai;

  • 作者单位

    Department of Neurophysiology Gunma University Graduate School of Medicine Maebashi Gunma 371-8511 Japan;

    Department of Neurophysiology Gunma University Graduate School of Medicine Maebashi Gunma 371-8511 Japan;

    Department of Neurophysiology Gunma University Graduate School of Medicine Maebashi Gunma 371-8511 Japan;

    Department of Neurophysiology Gunma University Graduate School of Medicine Maebashi Gunma 371-8511 Japan;

    Department of Neurophysiology Gunma University Graduate School of Medicine Maebashi Gunma 371-8511 Japan;

    Department of Neurophysiology Gunma University Graduate School of Medicine Maebashi Gunma 371-8511 Japan;

    Department of Neurophysiology Gunma University Graduate School of Medicine Maebashi Gunma 371-8511 Japan;

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  • 正文语种 eng
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  • 关键词

    Lentivirus; Dendrite; Purkinje cell; Cerebellum; Development; Gene therapy;

    机译：慢病毒;树突;浦肯野细胞;小脑;发育;基因治疗;

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