SHANK3和IGF1恢复了22q13删除综合征患者神经元中的突触缺陷
Aleksandr Shcheglovitov1, Olesya Shcheglovitova, Masayuki Yazawa
1Department of Neurobiology, Stanford University, Stanford, California 94305, USA.
Nature
|October 18, 2013
概括
费兰-麦克德米德综合征 (PMDS) 神经元显示出由于SHANK3.3减少而导致刺激性突触传输受损. 恢复SHANK3或使用IGF1可以纠正这些缺陷,为PMDS和相关的神经发育障碍提供潜在的治疗途径.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 发展生物学 发展生物学
背景情况:
- 费兰-麦克德米德综合征 (PMDS) 是一种由22q13.3删除引起的神经发育障碍,通常涉及SHANK3基因.
- SHANK3突变与自闭症谱系障碍 (ASD) 和智力障碍有关,但PMDS神经元中的细胞表型尚不清楚.
- 了解PMDS的分子基础对于开发向疗法至关重要.
研究的目的:
- 研究来自PMDS患者的人类神经元的细胞和分子表型.
- 确定SHANK3在PMDS中的突触功能中的作用.
- 确定潜在的治疗策略,以纠正PMDS中的突触缺陷.
主要方法:
- 从PMDS患者和健康对照组中生成诱导多能干细胞 (iPS).
- 将iPS细胞分化为功能的人类神经元.
- 电生理学记录以评估突触传输 (刺激和抑制).
- 对SHANK3表达和后突触密度蛋白位址的分析.
主要成果:
- 在PMDS神经元中,SHANK3表达显著减少.
- 在PMDS神经元中观察到激发性突触传播的缺陷,而抑制性传播基本上不受影响.
- 恢复SHANK3表达或用胰岛素样生长因子1 (IGF1) 治疗可以纠正激发性突触缺陷.
- IGF1治疗促进了成熟刺激性突触的形成.
结论:
- 由于SHANK3缺乏,PMDS神经元的激发抑制平衡被破坏.
- 在人类神经元中,SHANK3在激发性突触功能中起着至关重要的作用.
- 通过调节突触可塑性,IGF1代表了菲兰-麦克德米德综合征的潜在治疗标.
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