Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Interdepartmental Neuroscience Program

First Advisor

Koleske, Anthony

Abstract

Neurodevelopmental disorders (NDDs) affect the normal development and function of the brain, and include disorders such as autism spectrum disorder, intellectual disability, schizophrenia, bipolar disorder, and epilepsy. While these are diagnostically distinct disorders, NDDs share considerable comorbidities and present with overlapping symptoms. In addition, the risk genes for NDDs overlap significantly, further suggesting shared underlying pathology of these disorders. Mutations in the gene TRIO are enriched in individuals with neurodevelopmental disorders. TRIO encodes a large multidomain protein with two guanine nucleotide exchange factor domains for the Rho family of small GTPases and a putative kinase domain, as well as multiple accessory and protein-protein interacting domains. As a dual RhoGEF, TRIO integrates signals downstream of cell surface receptors and acts on GTPases to coordinate cytoskeletal rearrangements critical for proper neurodevelopment. Given the wide spectrum of TRIO variants associated with different pathological conditions, a fundamental and unresolved question is how distinct TRIO variants differentially impact mammalian brain development. In this thesis, I will describe my work investigating the multiple mechanisms by which TRIO regulates normal neurodevelopment and how discrete TRIO variants affecting TRIO’s biochemical functions contributes to neurodevelopmental disease-associated phenotypes.In Chapter 1, I set up the context for my thesis work with a review of TRIO's protein structure and biochemical functions, its roles in multiple aspects of neurodevelopment as described in knockout model organisms and in vitro studies, and the landscape of TRIO genetic variation that suggests a genotype-phenotype correlation in TRIO-associated neurodevelopmental disorders. Chapter 2 describes published work from our lab showing the effect of forebrain excitatory neuron-specific knockout of Trio in a haploinsufficiency mouse model. These mice have significantly abnormal behavior associated with neurodevelopmental disorders, severe neuromorphological changes to neurons, dendrites, and spines, and substantial excitatory pre- and post-synaptic transmission defects. Chapter 3 describes my co-first author work, which was recently submitted for publication, on mice harboring discrete heterozygous disease-associated Trio genetic variants. These mutations target different catalytic functions of Trio or alter Trio protein levels in the brain, leading to both overlapping and distinct alterations in behavior, neuromorphology, inhibitory and excitatory synaptic transmission defects, and brain proteomes. Chapter 4 describes unpublished work identifying decreased levels of Lgi1 resulting from Trio deficiency or dysfunction. I cover my work developing tools for studying a Trio-Lgi1 protein interaction and preliminary results from experiments dissecting how they may interact with each other. In Chapter 5, I discuss additional unpublished work to understand what other signaling pathways or neurodevelopment-associated processes Trio may be involved in. This preliminary work will highlight the most immediate pressing experiments to follow up my thesis work leading to future discoveries of Trio function in neurodevelopment.

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