Assembly of functionally integrated human forebrain spheroids

By Fikri Birey, Jimena Andersen, Christopher D. Makinson, S. Islam, Wu Wei, Nina Huber, H. C. Fan, K. R. C. Metzler, Georgia Panagiotakos, Nicholas Thom and 6 more. Nature, 2017

1,162 citations recorded by the source corpus.

The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-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 CaV1.2 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.

Subfields: Cellular and Molecular Neuroscience, Developmental Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b7224e2ddc6ec6522533c6d5e34a1efd9f6daa77

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Citations in the corpus

Brain organoids: advances, applications and challenges (2019, methodology): “Synaptogenesis also appears to be abundant when examined using immunostaining or electron microscopy (Birey et al., 2017; Pasca et al., 2015; Quadrato et al., 2017; Sloan et al., 2017).”
Complex oscillatory waves emerging from cortical organoids model early human brain network development (2019, background): “Despite recent advances in the understanding of their cellular diversity, there is no evidence that these organoids develop complex and functional neural network activity that resembles early human brain formation (Birey et al., 2017; Giandomenico et al., 2019; Quadrato et al., 2017).”