Date of Award

Spring 5-2023

Degree Type

Thesis

Director of Thesis

Dr. Kristy Welshhans, Ph.D.

Second Reader

Dr. Manasi Agrawal, Ph.D.

Abstract

Down syndrome (DS) is a complex neurodevelopmental disorder caused by the trisomy of chromosome 21. DS is the largest genetic cause of intellectual disability, which occurs in varying severity among affected individuals. It is associated with a variety of developmental and cognitive defects, including reduced brain size, impaired synaptic function, and altered neuronal morphology. A number of genes have been identified to play critical roles in the development and maintenance of neuronal morphology, and alterations in the expression of some of these genes are implicated in the morphological changes observed in DS. Knocking out or altering their expression leads to significant changes in dendritic length, spine density, and branching complexity, providing further evidence for their role in DS pathophysiology. Specifically, Down syndrome cell adhesion molecule (DSCAM) is located on chromosome 21 and known to regulate neuronal development and synaptic connectivity. Recent advances in stem cell technology have enabled the generation of human induced pluripotent stem cell (hiPSC)-derived neurons, providing a powerful tool for studying the genetic mechanisms underlying DS pathophysiology. Herein, morphological changes in DS human induced pluripotent stem cell (hiPSC)-derived neurons are quantified, and the contribution of DSCAM to these changes is examined. In this study, we use hiPSCs from an individual with DS and isogenic control hiPSCs and differentiate them into glutamatergic cortical neurons. First, we find that there are morphological changes in developing Down syndrome hiPSC-derived glutamatergic neurons, as compared to isogenic control neurons. We also find that there is an increased expression of DSCAM in DS neurons. Next, a siRNA knockdown of the human DSCAM gene was performed, to reduce levels of DSCAM to those found in isogenic control neurons, but the knockdown was unsuccessful. Overall, this study highlights the importance of studying the genetic mechanisms underlying DS pathophysiology using hiPSC-derived neurons. This paper also reviews recent studies investigating other genes responsible for such neuronal alterations. The identification and investigation of candidate genes involved in altered neuronal morphogenesis in DS may lead to the development of novel therapies for this disorder. Our findings suggest that targeting DSCAM may be a potential therapeutic approach for improving neuronal morphology in DS.

First Page

1

Last Page

58

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