来自美国斯克里普斯研究所神经科学系的Gavin Rumbaugh实验室发现致病的SYNGAP1突变通过破坏树突棘突触来损伤智力发育,这篇文章刊登在最新一期《CELL》杂志上。

-2012年11月9日《细胞》


中文翻译


【题目】致病的SYNGAP1突变通过破坏树突棘突触来损伤智力发育

【译文】引起智障(ID)和孤独症(ASD)的突变基因通常是编码染色体接合蛋白的。然而,现在还不清楚这些突变是怎样使得染色体接合蛋白功能丧失从而损伤智力的。在患有ID/ASD的SYNGAP1小鼠模型中,我们发现在早期产后早期阶段树突棘突触发育的过早。在发育的海马中,过早成熟的脊椎显著提高了兴奋性,这与出现的行为异常情况一致。在重要的发育窗口关闭后,诱导的SYNGAP1突变最小程度的伤害脊椎棘突触的功能,但是在成人期修复这些致病的突变体没有提高行为和认知。这些数据表明SynGAP蛋白作为神经元兴奋性一个重要的发育抑制子可以促进终生认知能力发育。我们认为在生命早期树突棘突触成熟的速度对于正常智力发育有重要的决定性作用。

英文原稿


[Title]Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses

[Authors]James P. Clement, Massimiliano Aceti, Thomas K. Creson, Emin D. Ozkan, Yulin Shi, Nicholas J. Reish, Antoine G. Almonte, Brooke H. Miller, Brian J. Wiltgen, Courtney A. Miller, Xiangmin Xu, Gavin Rumbaugh

[Abstract]Mutations that cause intellectual disability (ID) and autism spectrum disorder (ASD) are commonly found in genes that encode for synaptic proteins. However, it remains unclear how mutations that disrupt synapse function impact intellectual ability. In the SYNGAP1 mouse model of ID/ASD, we found that dendritic spine synapses develop prematurely during the early postnatal period. Premature spine maturation dramatically enhanced excitability in the developing hippocampus, which corresponded with the emergence of behavioral abnormalities. Inducing SYNGAP1 mutations after critical developmental windows closed had minimal impact on spine synapse function, whereas repairing these pathogenic mutations in adulthood did not improve behavior and cognition. These data demonstrate that SynGAP protein acts as a critical developmental repressor of neural excitability that promotes the development of life-long cognitive abilities. We propose that the pace of dendritic spine synapse maturation in early life is a critical determinant of normal intellectual development.

原文地址

http://www.cell.com/abstract/S0092-8674(12)01240-8

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