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Assembly of functionally integrated human forebrain spheroids

机译：功能集成的人类前脑球体的组装

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摘要

The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (gamma-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca(V)1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
机译：神经系统的发育涉及一系列协调的事件，包括GABA能神经元（γ-氨基丁酸释放）从腹侧到背侧前脑的迁移以及它们整合到皮层回路中。但是，这些区域间的相互作用尚未用人类细胞进行建模。在这里，我们从人多能干细胞中产生了三维球体，它们类似于背侧或腹侧前脑，并含有皮质谷氨酸能或GABA能神经元。这些亚域特定的前脑球体可以在体外组装，以概括在胎儿前脑中观察到的中间神经元的盐迁移。使用此系统，我们发现在蒂莫西综合征（一种由钙（V）1.2钙通道-interneurons突变引起的神经发育障碍）中显示出异常的迁徙盐分。我们还表明，迁移后，interneurons功能与谷氨酸能神经元整合形成一个微生理系统。我们预计这种方法将对研究神经发育和疾病，以及推导类似于其他大脑区域的球体以在体外组装电路很有用。

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  • 来源
    《Nature》 |2017年第7652期|54-59|共6页
  • 作者

    Birey Fikri; Andersen Jimena; Makinson Christopher D.; Islam Saiful; Wei Wu; Huber Nina; Fan H. Christina; Metzler Kimberly R. Cordes; Panagiotakos Georgia; Thom Nicholas; ORourke Nancy A.; Steinmetz Lars M.; Bernstein Jonathan A.; Hallmayer Joachim; Huguenard John R.; Pasca Sergiu P.;

  • 作者单位

    Stanford Univ, Sch Med, Ctr Sleep Sci & Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA;

    Stanford Univ, Sch Med, Ctr Sleep Sci & Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA;

    Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA;

    Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA;

    Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA|Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA;

    Stanford Univ, Sch Med, Ctr Sleep Sci & Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA;

    BD Genom, Menlo Pk, CA 94025 USA;

    BD Genom, Menlo Pk, CA 94025 USA;

    Univ Calif San Francisco, Dept Biochem & Biophys, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA;

    Stanford Univ, Sch Med, Ctr Sleep Sci & Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA;

    Stanford Univ, Sch Med, Ctr Sleep Sci & Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA;

    Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA|Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA|EMBL, Genome Biol Unit, D-69117 Heidelberg, Germany;

    Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA;

    Stanford Univ, Sch Med, Ctr Sleep Sci & Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA;

    Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA;

    Stanford Univ, Sch Med, Ctr Sleep Sci & Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA;

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