Editors' ChoiceDown’s Syndrome

A bit too much Olig2 in Down’s syndrome

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Science Translational Medicine  05 Jun 2019:
Vol. 11, Issue 495, eaay1425
DOI: 10.1126/scitranslmed.aay1425


Overproduction of the Olig2 gene responsible for cerebral cortex neurotransmission may explain cognitive impairment in Down’s syndrome.

About 1 in 700 babies are born with Down’s syndrome (DS), a form of intellectual disability caused by triplication of the chromosome 21. Disruption in forebrain development has been reported in patients with DS, including changes in neurotransmission in the cerebral cortex, although the underlying causes are not completely understood. Here, Xu et al. demonstrate that overexpression of the gene Olig2, a marker for GABAergic interneuron development found in chromosome 21, may underlie these neurological changes.

To study the neurodevelopmental changes associated with DS, the investigators grew ventral forebrain organoids from induced pluripotent stem cells (iPSCs) derived from patients with DS. Compared with control organoids, the forebrain organoids generated from DS-iPSCs abnormally overexpress the Olig2 gene, which was associated with an overproduction of inhibitory GABAergic interneurons. Silencing of Olig2 expression by introducing a short hairpin RNA (shRNA) reversed those changes. RNA-sequencing analysis of the iPSC-generated DS organoids demonstrated that many of the genes critical to GABAergic interneuron differentiation were also up-regulated, whereas RNA-sequencing of Olig2 shRNA expressing organoids partially reversed those gene expression changes.

These observations were followed up with a chimeric mouse model, in which the human ventral forebrain organoids were engrafted into the brains of immunodeficient mice. The investigators reported an overabundance of functional GABAergic interneurons in the DS chimeric mice, confirming the observations found in organoids. The chimeric mice with engrafted DS organoids expressing Olig2 shRNA also reversed the overproduction of GABAergic interneurons. To study the behavioral consequences of this increased GABAergic neurotransmission, memory recognition tests were performed on the DS chimeric mice. These mice displayed impairments in recognizing new objects, which was partially reversed in the chimeric mice with engrafted Olig2 shRNA forebrain organoids.

Owing to the lack of appropriate human-based models, this study elegantly demonstrates the potential for human forebrain organoids and chimeric mice to study the complex neurological mechanisms underlying DS. Future studies should expand on the roles of other forebrain neurons and glial cells affected by Olig2 overexpression in the neurological development of human DS. Understanding the genetic associations with neurological development can translate to rational therapeutic strategies to improve the cognitive impairment in DS.

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