Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors
Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors
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DOI：
10.1073/pnas.0707484104
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发表时间：
2007-09-25
影响因子：
11.1
通讯作者：
Warren, Stephen T.
中科院分区：
文献类型：
--
作者：
Nakamoto, Mika;Nalavadi, Vijayalaxmi;Warren, Stephen T.
脆性X综合征（FXS）是一种常见的遗传性智力低下，是由脆性X智力低下蛋白（FMRP）的功能缺失引起的，FMRP是一种rna结合蛋白，调节突触中特定mrna的翻译。小鼠FXS模型中描述了突触可塑性的改变。然而，FMRP缺失改变突触功能并随后导致精神损伤的机制尚不清楚。在培养的海马神经元中，我们使用sirna对抗Fmr1来证明树突中FMRP的减少会导致树突中a-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）亚基GluR1的内化增加。这种异常的AMPAR运输是由自发动作电位驱动的网络活动引起的，没有外源性激动剂的突触刺激，并由mglur5特异性逆激动剂2-甲基-6-苯基乙基吡啶（MPEP）挽救。由于AMPAR内化依赖于mGluR5刺激后的局部蛋白质合成，FMRP（翻译的负调节因子）可能被视为一种平衡信号，其中FMRP的缺失导致树突中mGluR5信号的明显过剩。由于AMPAR运输是学习和记忆基础上突触可塑性的驱动过程，我们的数据表明，响应过量mGluR信号的超敏感AMPAR内化可能是FXS的主要细胞缺陷，可以通过使用mGluR拮抗剂来纠正。
Fragile X syndrome (FXS), a common inherited form of mental retardation, is caused by the functional absence of the fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates the translation of specific mRNAs at synapses. Altered synaptic plasticity has been described in a mouse FXS model. However, the mechanism by which the loss of FMRP alters synaptic function, and subsequently causes the mental impairment, is unknown. Here, in cultured hippocampal neurons, we used siRNAs against Fmr1 to demonstrate that a reduction of FMRP in dendrites leads to an increase in internalization of the a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit, GluR1, in dendrites. This abnormal AMPAR trafficking was caused by spontaneous action potential-driven network activity without synaptic stimulation by an exogenous agonist and was rescued by 2-methyl-6-phenylethynyl-pyridine (MPEP), an mGluR5specific inverse agonist. Because AMPAR internalization depends on local protein synthesis after mGluR5 stimulation, FMRP, a negative regulator of translation, may be viewed as a counterbalancing signal, wherein the absence of FMRP leads to an apparent excess of mGluR5 signaling in dendrites. Because AMPAR trafficking is a driving process for synaptic plasticity underlying learning and memory, our data suggest that hypersensitive AMPAR internalization in response to excess mGluR signaling may represent a principal cellular defect in FXS, which may be corrected by using mGluR antagonists.