Graduation Year
2026
Date of Submission
12-2025
Document Type
Open Access Senior Thesis
Degree Name
Bachelor of Arts
Department
Neuroscience
Reader 1
Dr. Xiao Zhang
Reader 2
Dr. Alex Pollen
Terms of Use & License Information
Rights Information
@2025 Andrew Yuan
Abstract
Down syndrome (DS), caused by Trisomy 21, is the most common genetic cause of intellectual disability. Individuals with DS consistently show reduced brain volume, decreased cortical thickness, and lasting impairments in learning, memory, and executive functioning. These neuroanatomical changes emerge during fetal development and are accompanied by chronic immune dysregulation due to the triplication of four interferon receptor genes on chromosome 21. Although decreased neuron progenitor proliferation has been known to contribute to these phenotypes, the precise timing and cellular mechanisms underlying disruptions in neurogenesis remain not fully understood. This study used immunohistochemistry to examine human fetal cortical tissue from gestational weeks (GW) 14-24, comparing Trisomy 21 and control samples. We observed a significant increase in inhibitory neurons and an elevated inhibitory to excitatory neuron ratio in Trisomy 21 tissue during early mid-gestation (GW14-18). These findings point towards precocious inhibitory neurogenesis that disrupts the normal excitatory to inhibitory neuron balance during human fetal cortical development. To explore potential underlying mechanisms, we tested the contribution of interferon and JAK-STAT signaling using human fetal organotypic slice cultures. Treatment with recombinant IFNβ tended to reduce excitatory neuron production while JAK inhibitor Tofacitinib significantly increased excitatory neuron production which partially restored the inhibitory to excitatory neuronal balance. These results suggest that Trisomy 21 accelerates inhibitory neurogenesis in the human fetal brain which is likely driven in part by elevated levels of interferon signaling. Pharmacological inhibition of the JAK-STAT pathway could offer a promising potential therapeutic strategy to improve and restore cortical development in DS.
Recommended Citation
Yuan, Andrew, "From Imbalance to Phenotype: Neurodevelopmental Alterations in Trisomy 21" (2026). CMC Senior Theses. 4253.
https://scholarship.claremont.edu/cmc_theses/4253
