Mentor: Joseph Ransdell, Ph.D.

Autism spectrum disorder (ASD), despite occurring relatively frequently compared to most neurodevelopmental disorders, has remained challenging to study due to its multifaceted pathogenesis and resulting difficulties around modeling the disease. Despite this, a promising mouse model does exist that takes advantage of the TSC1 gene. Mutations in this gene follow an autosomal dominant pattern of inheritance in humans and lead to faulty mTORC1 signaling, leading to tuberous sclerosis, a debilitating condition that affects multiple systems of the body. Over 50% of humans with tuberous sclerosis also happen to meet diagnostic criteria for ASD, making mutations of this gene a critical tool for potentially modeling ASD behaviors. There exists a mouse model with targeted deletion via a Cre recombinase system of the TSC1 gene in cerebellar Purkinje neurons, and homozygous mutants have been shown to suffer motor coordination and sociability deficits when compared to wild type mice. However, there have been conflicting findings on the heterozygous mutant for this mouse model when compared to wild types, warranting further investigation into the autosomal dominant nature of this mutation in the mouse model. Thus, in this study, we utilized an open field and three-chamber social task hybrid assay and an elevated balance beam test to investigate deficits in the heterozygous mouse model. We found that the heterozygous mice exhibit virtually no differences in sociability when compared to wild type mice, and exhibit motor coordination that is equal to or even better than wild type mice. Our findings strongly indicate that the autosomal dominance in the TSC1 gene mutations that is observed in humans does not translate to the mouse model, and caution is advised when drawing conclusions about the condition in humans from the heterozygous mice.

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