Investigating the Neurodevelopmental Effects of Autism Risk Gene, PTEN, in Zebrafish

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

Hoffman, Ellen

Abstract

The lack of effective treatments for autism spectrum disorder (ASD) and other neurodevelopmental disorders including congenital hydrocephalus (CH), reflect the limited understanding of the underlying biology. Although ASD and CH have been extensively studied as independent entities, recent human genomic and pre-clinical animal studies have uncovered shared molecular pathophysiology. Here, we first review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN/PI3K/mTOR pathway as a common underlying mechanism that holds diagnostic, prognostic, and therapeutic promise for patients. Next, we model ptenab loss of function in zebrafish and assess early neurodevelopmental outcomes using cellular, molecular, pharmacological, and genetic techniques. We find that ptenab mutants display altered early temporal patterns of neural proliferation, and there are increases in GABAergic neuron populations, basal brain activity, and brain size. We use bulk RNAseq to identify increases in synaptic and neurogenic pathways, and downregulation in Wnt signaling and hormonal regulation pathways. Mutants display behavioral hypersensitivity to dark flash stimuli and altered rest-wake activity patterns. A pharmacological screen of anticorrelating psychoactive compounds showed targeting GPCRs, Wnt, hormonal signaling, and upstream mTOR pathway member, PI3K, rescues behavioral abnormalities. This study presents a new model for studying ptenab mutation in vertebrate neurodevelopment that is amenable to pharmacological screens, and identifies novel rescue compounds, which could inform therapeutic treatments.

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