Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome
Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome
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DOI：
10.1073/pnas.1013855108
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发表时间：
2011-02-08
影响因子：
11.1
通讯作者：
Bear, Mark F.
中科院分区：
文献类型：
--
作者：
Krueger, Dilja D.;Osterweil, Emily K.;Bear, Mark F.
据报道，脆性X综合征（FXS）患者的标志性表型包括注意力功能、抑制控制和认知灵活性（一组被认为与前额叶皮质（PFC）相关的认知技能）缺陷。然而，尽管对这些核心缺陷进行了大量的临床研究，但PFC在临床前研究中，特别是在FXS的动物模型中，很少受到关注。在这项研究中，我们试图调查的分子，细胞和行为的后果的损失的脆性X智力低下蛋白在PFC的Fmr 1基因敲除小鼠，FXS的小鼠模型。我们确定了这些小鼠的强大的认知障碍，这可能与FXS患者的认知灵活性缺陷有关。此外，我们报告，参与突触功能的蛋白质，包括NMDA受体亚基NR 1，NR 2A和NR 2B;支架蛋白PSD-95和SAPAP 3;和可塑性相关基因Arc的水平，在Fmr 1基因敲除小鼠的前额叶皮层中降低，并与行为表现部分相关。最后，我们报告说，表达的c-Fos，神经元活动的标志物，减少在PFC的Fmr 1基因敲除小鼠。总之，这些数据表明，Fmr 1基因敲除小鼠可能代表了一个有价值的动物模型PFC相关的分子，细胞和行为异常的FXS和该模型可能是有用的，用于测试疗效的治疗策略，旨在治疗FXS的认知障碍。
Among the hallmark phenotypes reported in individuals with fragile X syndrome (FXS) are deficits in attentional function, inhibitory control, and cognitive flexibility, a set of cognitive skills thought to be associated with the prefrontal cortex (PFC). However, despite substantial clinical research into these core deficits, the PFC has received surprisingly little attention in preclinical research, particularly in animal models of FXS. In this study, we sought to investigate the molecular, cellular, and behavioral consequences of the loss of the fragile X mental retardation protein in the PFC of Fmr1 KO mice, a mouse model of FXS. We identify a robust cognitive impairment in these mice that may be related to the deficits in cognitive flexibility observed in individuals with FXS. In addition, we report that levels of proteins involved in synaptic function, including the NMDA receptor subunits NR1, NR2A, and NR2B; the scaffolding proteins PSD-95 and SAPAP3; and the plasticity-related gene Arc, are decreased in the prefrontal cortex of Fmr1 KO mice and are partly correlated with behavioral performance. Finally, we report that expression of c-Fos, a marker of neuronal activity, is decreased in the PFC of Fmr1 KO mice. Together, these data suggest that Fmr1 KO mice may represent a valuable animal model for the PFC-associated molecular, cellular, and behavioral abnormalities in FXS and that this model may be useful for testing the efficacy of therapeutic strategies aimed at treating the cognitive impairments in FXS.