Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome.
Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome.
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DOI：
10.1523/jneurosci.1496-08.2008
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发表时间：
2008-07-30
期刊：
影响因子：
--
通讯作者：
Zhu JJ
中科院分区：
文献类型：
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作者：
Hu H;Qin Y;Bochorishvili G;Zhu Y;van Aelst L;Zhu JJ
脆性X综合征是由FMR1基因功能丧失和脆性X智力低下蛋白(FMRP)丢失引起的，是最常见的遗传性智力低下形式。该综合征的特点是联想学习障碍，癌症风险降低，树突棘畸形和面部畸形。然而，FMR1功能丧失与学习障碍之间的分子机制尚不清楚。在这里，我们报告了小GTP酶、RAS信号和突触AMPA受体(-Rs)在野生型和FMR1基因敲除小鼠的培养切片和完整脑中的运输情况。在FMR1基因敲除小鼠中，GluR1-的突触传递受到损害，但包含GluR2L和GluR4的AMPA-Rs的突触传递受到损害，导致选择性丧失依赖GluR1的长期突触增强(LTP)。在FMR1基因敲除小鼠中，虽然RAS活性上调，但其下游的细胞外信号调节激酶(MEK)-细胞外信号调节激酶(ERK)信号转导正常，而磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(PKB或Akt)信号转导受到抑制。在FMR1基因敲除小鼠中，增强RAS-PI3K-PKB信号可恢复含有GluR1的AMPA-Rs和正常LTP的突触传递。这些结果提示RAS信号异常是脆性X综合征的一种新机制，并提示操纵RAS-PI3K-PKB信号通路是治疗脆性X综合征的一种潜在的有效方法。
Fragile X syndrome, caused by the loss of FMR1 gene function and loss of fragile X mental retardation protein (FMRP), is the most commonly inherited form of mental retardation. The syndrome is characterized by associative learning deficits, reduced risk of cancer, dendritic spine dysmorphogenesis and facial dysmorphism. However, the molecular mechanism that links loss of function of FMR1 to the learning disability remains unclear. Here we report an examination of small GTPase Ras signaling and synaptic AMPA receptor (-Rs) trafficking in cultured slices and intact brains of wild type and FMR1 knockout mice. In FMR1 knockout mice, synaptic delivery of GluR1-, but not GluR2L- and GluR4-containing AMPA-Rs is impaired, resulting in a selective loss of GluR1-dependent long-term synaptic potentiation (LTP). Although Ras activity is up-regulated, its downstream extracellular signal-regulated kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) signaling appears normal and phosphoinositide 3-kinase (PI3K)–protein kinase B (PKB or Akt) signaling is compromised in FMR1 knockout mice. Enhancing Ras–PI3K–PKB signaling restores synaptic delivery of GluR1-containing AMPA-Rs and normal LTP in FMR1 knockout mice. These results suggest aberrant Ras signaling as a novel mechanism for fragile X syndrome and indicate manipulating Ras–PI3K–PKB signaling to be a potentially effective approach for treating patients with fragile X syndrome.