Date of Award
Doctor of Philosophy (PhD)
The Williams Syndrome Critical Region (WSCR) at chromosome 7q11.23 provides a unique opportunity to untangle the relationship between genotype and phenotype in complex behaviors, from fear and anxiety to sociability and sensorimotor processing. Copy number variations (CNVs) in this region result in two syndromes, Williams Syndrome (WS) and Duplication 7q11.23 Syndrome (Dup7), which display phenotypes that may align, indicating a common disruption of a system, or diverge, reflecting an underlying gene dosage-dependent effect. While case studies of atypical deletions resulting in WS have implicated telomeric genes Gtf2ird1 and Gtf2i in the cognitive and behavioral profiles of WS, proving causation requires utilizing mouse models. Thus, I leveraged the construct validity of a mouse line modeling the most common deletion in WS to assess pharmacological and genetic interventions in an attempt to ameliorate deficits caused by CNVs in the WSCR. I assessed the role of oxytocin in fear conditioning deficits observed in the Complete Deletion (CD) mice and show that an oxytocin antagonist delivered to the central nervous system does not rescue the contextual and cued recall impairments, suggesting no direct role for oxytocin dysregulation in these features of the CD model. No significant differences in oxytocin receptor density or distribution were found either. I then present a novel transgenic model designed to overexpress Gtf2ird1, one of the genes implicated in the hallmark cognitive and behavioral features of WS and characterize the effect of its overexpression on a C57BL/6J wild type background and its molecular rescue of Gtf2ird1 expression on the CD background in a comprehensive assessment of sensorimotor, anxiety, fear, and social behaviors. Deficits in the CD model are shown in all of these domains to various degrees and while Gtf2ird1 did not play a role in the enhanced social approach or motivation observed in the CD line, it did ameliorate deficits in three tasks (Platform, Rotarod and Light/Dark box). These results may support the idea that Gtf2ird1 is involved in sensory processing, which has been suggested particularly regarding the visuospatial deficits seen in WS.
Chair and Committee
Nygaard, Kayla Rose, "Extensive Behavioral Phenotyping of Williams Syndrome Locus Relevant Mouse Models to Assess Contributions of Oxytocin and Gtf2ird1" (2022). Arts & Sciences Electronic Theses and Dissertations. 2778.