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Neuron:Syngap1基因突变如何导致早期脑损伤

来源:生物谷 2014-06-23 09:08

2014年6月23日讯 /生物谷BIOON/--近日,来自佛罗里达斯克里普斯科学家们揭示了一种特定类型的基因突变如何可以在大脑早期发育造成损害,导致终身学习和行为障碍。这项研究的重点是Syngap1基因的作用,研究论文发表在Neuron杂志上。在人类中,Syngap1突变已知会造成毁灭性形式的智力残疾和癫痫。

这项研究领导者Gavin Rumbaugh解释:我们发现了一个敏感的细胞类型,其对于Syngap1突变引起的大部分行为问题是必要和充分的。我们发现这种遗传性脑部疾病的根本生物原因,因此现在可以开发新的疗法来治疗Syngap1突变的人。

在这项研究中,Rumbaugh和他的同事使用了一种小鼠模型表明,Syngap1突变破坏了年轻前脑中谷氨酸能神经元的发育,导致智力残疾。众所周知,随着孩子的前脑发育,会出现较高的认知过程,如语言,推理和记忆。

在发育过程中修复这些特定神经元中Syngap1突变能阻止认知异常,而修复其他类型的神经元基因没有此效果。Rumbaugh注意到,一些婴幼儿遗传性疾病的产前诊断即将来临,基因测序技术的进步允许扫描个体基因组中破坏性突变,它可以扫描仍然在子宫内的孩子的整个基因组。(生物谷Bioon.com)

Reduced Cognition in Syngap1 Mutants Is Caused by Isolated Damage within Developing Forebrain Excitatory Neurons.

Emin D. Ozkan, Thomas K. Creson, Enik? A. Kramár, Camilo Rojas, Ron R. Seese, Alex H. Babyan, Yulin Shi, Rocco Lucero, Xiangmin Xu, Jeffrey L. Noebels, Courtney A. Miller, Gary Lynch, Gavin Rumbaugh.

Syngap1 haploinsufficiency is a common cause of sporadic intellectual disability. Syngap1 mutations disrupt developing pyramidal neurons, although it remains unclear if this process contributes to cognitive abnormalities. Here, we found that haploinsufficiency restricted to forebrain glutamatergic neurons was sufficient to disrupt cognition and removing mutations from this population prevented cognitive abnormalities. In contrast, manipulating Syngap1 function in GABAergic neurons had no effect on cognition, excitability, or neurotransmission, highlighting the specificity of Syngap1 mutations within forebrain excitatory neurons. Interestingly, cognitive abnormalities were reliably predicted by the emergence of enhanced excitatory synaptic function in mature superficial cortical pyramidal cells, which was a neurophysiological disruption caused by Syngap1 dysfunction in developing, but not adult, forebrain neurons. We conclude that reduced cognition in Syngap1 mutants is caused by isolated damage to developing forebrain glutamatergic neurons. This damage triggers secondary disruptions to synaptic homeostasis in mature cortical pyramidal cells, which perpetuates brain dysfunction into adulthood.

 

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