Dissertation

Modeling Neurodevelopmental and Psychiatric Disorders Using Induced Pluripotent Stem Cells: Exploring Cellular Mechanisms and Therapeutic Insights

Nayak, Ritu

2025

Overview

Neurodevelopmental and psychiatric disorders, such as Autism Spectrum Disorder (ASD) and Bipolar Disorder (BD), have been linked to genetic and molecular changes that disrupt normal brain function and development. These disorders often involve complex interactions between genes and environmental factors, leading to significant cognitive and emotional dysregulation. In this thesis, my findings demonstrate that hippocampal neurons carrying the SLC1A4mutation exhibit early maturation, characterized by heightened synaptic activity and excitability during early developmental stages compared to healthy controls. However, as these neurons age, their excitability significantly decreases. Clinically, the SLC1A4mutation is associated with symptoms such as developmental delays, intellectual disability (ID), speech impairments, hypotonia (reduced muscle tone), and motor dysfunction, reflecting the broad impact of this mutation on both cognitive and physical development. This pattern of early hyperexcitability followed by reduced neuronal activity over time mirrors phenotypes observed in other ASD-associated mutations. The metabolic profiling data further supports these electrophysiological findings, shedding light on the underlying biochemical alterations specifically, revealing alterations in energy metabolism, neurotransmitter precursors, and other metabolites that are critical for SLC1A4function. Additionally, this thesis also delves into Smith-Magenis Syndrome (SMS), which is caused by a deletion or mutation in the RAI1gene and is linked to ID, sleep disturbances, and behavioral abnormalities. The study shows a promising response to retinoic acid (RA) treatment, which ameliorates some of the deficits in excitability and synaptic function observed in SMS-mutant neurons.Beyond neurodevelopmental studies, the thesis delves into RNA sequencing analysis of lymphoblastoid cell lines (LCLs) from BD patients to investigate genetic signatures associated with suicide risk. Differentially expressed genes (DEGs) identified in high-risk suicide patients reveal significant involvement in pathways related to immune, ion channel, and cardiovascular dysfunctions. Machine learning (ML) models developed in the study demonstrate high predictive accuracy for suicide risk in BD. This comprehensive approach advances our understanding of both neurodevelopmental disorder: SLC1A4and RAI1mutation and psychiatric disorder such as BD facets of disorders, offering new molecular insights and potential therapeutic strategies.

• Publisher: ProQuest Dissertations & Theses
• Subject: Autism / Behavioral psychology / Bipolar disorder / Clinical psychology / Disability studies / Genetics / Genomics / Hyperactivity / Mental disorders / Mental health / Stem cells
• ISBN: 9798283484945