Defective AMPA-mediated synaptic transmission and morphology in human neurons with hemizygous SHANK3 deletion engrafted in mouse prefrontal cortex.
Defective AMPA-mediated synaptic transmission and morphology in human neurons with hemizygous SHANK3 deletion engrafted in mouse prefrontal cortex.
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移植到小鼠前额叶皮层的半合子SHANK3缺失的人类神经元中AMPA介导的突触传递和形态学缺陷
DOI：
10.1038/s41380-021-01023-2
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发表时间：
2021-09
影响因子：
11
通讯作者：
Shcheglovitov A
中科院分区：
文献类型：
--
作者：
Chiola S;Napan KL;Wang Y;Lazarenko RM;Armstrong CJ;Cui J;Shcheglovitov A
突触蛋白的遗传异常在自闭症患者中很常见；然而，我们对这些异常扰乱的细胞和分子机制的了解有限。SHANK3是一种兴奋性突触的突触后支架蛋白，在大多数22q13缺失综合征患者和约2%的特发性自闭症和智能障碍患者中发现了突变或缺失。在这里，我们构建了带有SHANK3基因缺失(SHANK3+/−)的CRISPR/CAS9工程人多能干细胞(PSC)，这是患者中最常见的遗传异常，并研究了SHANK3缺陷的PSC来源的皮质神经元的突触和形态特征。我们发现，人类PSC来源的神经元通过获得适当的皮质层身份以及通过接收和发送来自/向多个不同大脑区域的解剖投影来整合到小鼠的皮质。我们还证明，与移植在同一脑区的同基因对照神经元相比，SHANK3缺陷的人类神经元减少了AMPA-，而不是NMDA-或GABA介导的突触传递，并显示出树突和棘突受损。综上所述，本研究揭示了SHANK3半合在生理条件下不同发育阶段的人皮质神经元中造成的特定突触和形态缺陷，并验证了共植入对照和突变人神经元作为研究自闭症相关遗传性神经发育障碍连接缺陷的新平台的使用。
Genetic abnormalities in synaptic proteins are common in individuals with autism; however, our understanding of the cellular and molecular mechanisms disrupted by these abnormalities is limited. SHANK3 is a postsynaptic scaffolding protein of excitatory synapses that has been found mutated or deleted in most patients with 22q13 deletion syndrome and about 2% of individuals with idiopathic autism and intellectual disability. Here, we generated CRISPR/Cas9-engineered human pluripotent stem cells (PSC) with complete hemizygous SHANK3 deletion (SHANK3+/−), which is the most common genetic abnormality in patients, and investigated the synaptic and morphological properties of SHANK3-deficient PSC-derived cortical neurons engrafted in the mouse prefrontal cortex. We show that human PSC-derived neurons integrate into the mouse cortex by acquiring appropriate cortical layer identities and by receiving and sending anatomical projections from/to multiple different brain regions. We also demonstrate that SHANK3-deficient human neurons have reduced AMPA-, but not NMDA- or GABA-mediated synaptic transmission and exhibit impaired dendritic arbors and spines, as compared to isogenic control neurons co-engrafted in the same brain region. Together, this study reveals specific synaptic and morphological deficits caused by SHANK3 hemizygosity in human cortical neurons at different developmental stages under physiological conditions and validates the use of co-engrafted control and mutant human neurons as a new platform for studying connectivity deficits in genetic neurodevelopmental disorders associated with autism.
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影响因子：
6.2
作者：
Bozdagi O;Sakurai T;Papapetrou D;Wang X;Dickstein DL;Takahashi N;Kajiwara Y;Yang M;Katz AM;Scattoni ML;Harris MJ;Saxena R;Silverman JL;Crawley JN;Zhou Q;Hof PR;Buxbaum JD
通讯作者：
Buxbaum JD
影响因子：
6.8
作者：
Bey AL;Wang X;Yan H;Kim N;Passman RL;Yang Y;Cao X;Towers AJ;Hulbert SW;Duffney LJ;Gaidis E;Rodriguiz RM;Wetsel WC;Yin HH;Jiang YH
通讯作者：
Jiang YH
影响因子：
4.8
作者：
Jin, Chunmei;Kang, Hyae Rim;Han, Kihoon
通讯作者：
Han, Kihoon
影响因子：
64.8
作者：
Fruchart, Michel;Zhou, Yujie;Vitelli, Vincenzo
通讯作者：
Vitelli, Vincenzo
影响因子：
16.2
作者：
Jiang YH;Ehlers MD
通讯作者：
Ehlers MD