Graduation Date

Fall 12-17-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Interdisciplinary Graduate Program in Biomedical Sciences

First Advisor

Anna Dunaevsky, PhD

MeSH Headings

humans, mice, fragile X syndrome, astrocytes, proteomics

Abstract

Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder related to intellectual disability and the most common monogenic cause of autism spectrum disorder. FXS is mainly caused by an expansion of CGG repeats in the 5’-untranslated region of fragile X mental retardation 1 (FMR1) gene, leading to the loss of expression of fragile X mental retardation protein (FMRP). Astrocytes are the most abundant glial cells in the central nervous system (CNS). Loss of FMRP in astrocytes has been found to contribute to structural and functional synaptic deficits in the Fmr1-KO mouse model. The contribution of human astrocytes, however, to the pathology of FXS remains unclear. Here, we developed a human-based astrocytes model of FXS and showed that the loss of FMRP could lead to altered development and Ca2+ activity in astrocytes. Furthermore, our proteomic analysis on astrocytes revealed human-specific molecular signatures associated with FXS. Several dysregulated cellular pathways were identified based on the altered proteomic profiles in FXS astrocytes, providing potential targets for the therapeutic research of FXS. Using the chimeric mouse model with engraftment of human astrocytes into the mouse cortex, we confirmed the altered Ca2+ activity of FXS astrocytes in vivo and identified the role of FXS astrocytes in altered structural synaptic regulation. Six months after engraftment, human astrocytes developed into interlaminar astrocytes in the mouse cortex, providing a model for studying the behavior and function of human-specific interlaminar astrocytes in the live brain. Here, our combined approach of characterizing human FXS astrocytes in vitro and in vivo in the chimeric mouse model highlights astrocytes as a novel therapeutic target of FXS treatment.

Available for download on Thursday, November 30, 2023

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