Using stem cells that can turn into other cells in the brain, researchers developed two experimental models -- a living 3D "organoid" model of the brain and a mouse brain model with implanted human cells -- to investigate early brain development linked to Down syndrome, according to the study in the journal Cell Stem Cell. The study focused on human chromosome 21 gene OLIG2.

"Our results suggest the OLIG2 gene is potentially an excellent prenatal therapeutic target to reverse abnormal embryonic brain development, rebalance the two types of neurons in the brain -- excitatory and inhibitory, and a healthy balance is critical -- as well as improve postnatal cognitive function," said Peng Jiang, assistant professor in the Department of Cell Biology and Neuroscience at Rutgers University-New Brunswick.

Usually, a baby is born with 46 chromosomes, but babies with Down syndrome have an extra copy of chromosome 21. That changes how a baby's body and brain develops, which can lead to mental and physical challenges, according to the U.S. Centers for Disease Control and Prevention. Down syndrome is the most common chromosomal condition diagnosed in the United States, affecting about one in 700 babies, and about 6,000 infants are born each year with the condition.

The researchers obtained skin cells collected from Down syndrome patients and genetically reprogrammed those cells to human-induced pluripotent stem cells (hiPSCs). Resembling embryonic stem cells, the special cells can develop into many different types of cells, including brain cells, during early life and growth and are useful tools for drug development and disease modeling, according to the National Institutes of Health.

Using brain cells derived from stem cells with an extra copy of chromosome 21, the scientists developed the 3D brain organoid model, which resembles the early developing human brain. They also developed the mouse brain model, with stem cell-derived human brain cells implanted into the mouse brain within a day after the mice were born. They found that inhibitory neurons -- which make your brain function smoothly -- were overproduced in both models, and adult mice had impaired memory. They also found that the OLIG2 gene plays a critical role in those effects and that inhibiting it led to improvements.

The combination of the brain organoid and mouse brain model could be used to study other neurodevelopmental disorders such as autism spectrum disorder. It may also help scientists better understand the mechanisms in Alzheimer's disease. Down syndrome patients often develop early-onset Alzheimer's disease, Jiang noted.

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Materials provided by Rutgers University. Note: Content may be edited for style and length.

Journal Reference:

1. Ranjie Xu, Andrew T. Brawner, Shenglan Li, Jing-Jing Liu, Hyosung Kim, Haipeng Xue, Zhiping P. Pang, Woo-Yang Kim, Ronald P. Hart, Ying Liu, Peng Jiang. OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome. Cell Stem Cell, 2019; DOI: 10.1016/j.stem.2019.04.014
2.