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It may one day be possible to reverse abnormal embryonic brain development linked to Down syndrome (DS) and improve cognitive function by therapeutically targeting a key gene known as OLIG2 prenatally, suggests newly published findings.



The study published in Cell Stem Cell sought to understand the mechanisms underlying imbalances in excitatory and inhibitory neurotransmission that may be responsible for cognitive defects in DS patients.



DS is a chromosomal condition that is linked to mild or moderate intellectual disability and affects people of all ages, races and economic situations. Patients with DS often experience a gradual decline in cognitive ability as they age. The condition is most frequently caused by trisomy 21 – whereby a person has three copies of chromosome 21 instead of two copies.



The team found that inhibitory neurons were overproduced in models of DS and that the OLIG2 gene was upregulated in DS neural progenitors. By reducing OLIG2 expression, it was possible to normalize inhibitory neuron production and behavioral deficits.



Corresponding author Peng Jiang, comments on the impact of the findings and how it has influenced their current research focus: “Based on the findings in this study, we are examining if normalizing OLIG2 expression – using OLIG2 small molecule inhibitors that have drug-like properties – would be able to correct overproduction of inhibitory neurons in a brain organoid model and help improve animal behavioral performance in a human neuronal chimeric mouse model.”



The researchers collected skin cells (specifically skin fibroblasts) from DS patients and converted them into human induced pluripotent stem cells (hiPSCs) – by delivering four defined reprogramming genes into the skin cells.





Why convert skin cells to hiPSCs?

Studying other neurodevelopmental disorders



