Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function
Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function
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DOI：
10.1073/pnas.1217665110
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发表时间：
2013-04-16
影响因子：
11.1
通讯作者：
Bartsch, Dusan
中科院分区：
文献类型：
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作者：
Tews, Bjoern;Schoenig, Kai;Bartsch, Dusan
我们已经用RNAi建立了一个转基因大鼠模型，并用它来研究膜蛋白Nogo-A在突触可塑性和认知中的作用。膜蛋白Nogo-A在中枢神经系统少突胶质细胞和神经元亚群中表达，它可以抑制神经突起的生长和再生。组成性表达的聚合酶II驱动的转基因是由一个针对Nogo-A的微小RNA组成的，它位于EGFP编码序列之前的内含子中，从而根据细胞内microRNA的表达对细胞进行定量标记。体内转基因microRNA有效地降低了神经元中Nogo-A的mRNA和蛋白浓度。由此导致的海马区和运动皮层的长时程增强显着增加，表明Nogo-A在突触可塑性中具有抑制作用。转基因大鼠表现出明显的精神分裂症样行为表型，如坚持不懈、脉冲前抑制中断和强烈退出社会互动。这种快速有效的microRNA介导的基因敲除为转基因大鼠体内基因表达的沉默提供了一种方法，并显示了Nogo-A在调节高级认知脑功能中的作用。
We have generated a transgenic rat model using RNAi and used it to study the role of the membrane protein Nogo-A in synaptic plasticity and cognition. The membrane protein Nogo-A is expressed in CNS oligodendrocytes and subpopulations of neurons, and it is known to suppress neurite growth and regeneration. The constitutively expressed polymerase II-driven transgene was composed of a micro-RNA-targeting Nogo-A placed into an intron preceding the coding sequence for EGFP, thus quantitatively labeling cells according to intracellular microRNA expression. The transgenic microRNA in vivo efficiently reduced the concentration of Nogo-A mRNA and protein preferentially in neurons. The resulting significant increase in long-term potentiation in both hippocampus and motor cortex indicates a repressor function of Nogo-A in synaptic plasticity. The transgenic rats exhibited prominent schizophrenia-like behavioral phenotypes, such as perseveration, disrupted prepulse inhibition, and strong withdrawal from social interactions. This fast and efficient micro-RNA-mediated knockdown provides a way to silence gene expression in vivo in transgenic rats and shows a role of Nogo-A in regulating higher cognitive brain functions.