Loss of the Fragile X Mental Retardation Protein Decouples Metabotropic Glutamate Receptor Dependent Priming of Long-Term Potentiation From Protein Synthesis
Loss of the Fragile X Mental Retardation Protein Decouples Metabotropic Glutamate Receptor Dependent Priming of Long-Term Potentiation From Protein Synthesis
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DOI：
10.1152/jn.00449.2010
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发表时间：
2010-08-01
影响因子：
2.5
通讯作者：
Bear, Mark F.
中科院分区：
文献类型：
--
作者：
Auerbach, Benjamin D.;Bear, Mark F.
奥尔巴赫BD，Bear MF。脆性X智力低下蛋白的缺失使依赖代谢性谷氨酸受体的长时程增强从蛋白质合成中解偶联。神经生理学杂志104：1047-1051,2010。2010年6月16日首次出版；DOI：10.1152/jn.00449.2010。脆性X综合征(FXS)是最常见的遗传性智力残疾形式，由脆性X智力低下蛋白(FMRP)丢失引起。FMRP是第1组代谢性谷氨酸受体(Gp1 MGluR)激活下游局部mRNA翻译的负调控因子。在没有FMRP的情况下，存在过度的mGluR依赖的蛋白质合成，导致海马区CA1区mGluR依赖的长期突触抑制(LTD)被夸大。了解疾病的病理生理学对于开发FXS的治疗方法至关重要，问题是针对过度的LTD或过度的mGluR依赖的蛋白质合成是否更合适。长时程增强(LTP)的启动是Gp1 mGluR刺激的蛋白质合成的一种本质上不同的功能结果，在同一群体的CA1突触中可以诱导LTP。因此，我们确定了LTP启动是否像LTD一样，在Fmr1基因敲除(KO)小鼠中也受到干扰。我们发现，野生型(WT)和Fmr1KO小鼠对LTP的mGluR依赖的启动具有类似的幅度。然而，尽管LTP启动需要WT小鼠蛋白质合成的急性刺激，但它不再依赖于Fmr1KO的蛋白质合成。这些实验表明，在Fmr1KO小鼠中看到的mGluR介导的蛋白质合成的失调对突触的可塑性有多种后果，即使在相同的突触群体中也是如此。此外，它还表明Gp1 mGluR信号通路存在一个分叉，一只手臂触发突触修饰，如LTP启动和LTD，另一只手臂刺激蛋白质合成，允许这些修饰。
Auerbach BD, Bear MF. Loss of the fragile X mental retardation protein decouples metabotropic glutamate receptor dependent priming of long-term potentiation from protein synthesis. J Neurophysiol 104: 1047-1051, 2010. First published June 16, 2010; doi: 10.1152/jn.00449.2010. Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). FMRP is a negative regulator of local mRNA translation downstream of group 1 metabotropic glutamate receptor (Gp1 mGluR) activation. In the absence of FMRP there is excessive mGluR-dependent protein synthesis, resulting in exaggerated mGluR-dependent long-term synaptic depression (LTD) in area CA1 of the hippocampus. Understanding disease pathophysiology is critical for development of therapies for FXS and the question arises of whether it is more appropriate to target excessive LTD or excessive mGluR-dependent protein synthesis. Priming of long-term potentiation (LTP) is a qualitatively different functional consequence of Gp1 mGluR-stimulated protein synthesis at the same population of CA1 synapses where LTD can be induced. Therefore we determined if LTP priming, like LTD, is also disrupted in the Fmr1 knockout (KO) mouse. We found that mGluR-dependent priming of LTP is of comparable magnitude in wild-type (WT) and Fmr1 KO mice. However, whereas LTP priming requires acute stimulation of protein synthesis in WT mice, it is no longer protein synthesis dependent in the Fmr1 KO. These experiments show that the dysregulation of mGluR-mediated protein synthesis seen in Fmr1 KO mice has multiple consequences on synaptic plasticity, even within the same population of synapses. Furthermore, it suggests that there is a bifurcation in the Gp1 mGluR signaling pathway, with one arm triggering synaptic modifications such as LTP priming and LTD and the other stimulating protein synthesis that is permissive for these modifications.