Degree

Doctor of Philosophy (PhD)

Department

Comparative Biomedical Sciences

Document Type

Dissertation

Abstract

Autism spectrum disorder (ASD) consists of a diverse group of developmental disabilities that result in heterogeneous behavioral phenotypes arising from abnormal neural development. ASD is comprised of various conditions characterized by alterations in social interaction, communication, and repetitive behaviors. Several factors contribute to the development of heterogenous autistic behaviors such as genetic and environmental factors. Mouse models of autism are useful in identifying genetic factors underlying human disorders and display ASD-like phenotypes. Substantial evidence has indicated alterations in cellular, synaptic, and neural circuit function resulting in autistic phenotype. Initially, we conducted review of neural mechanisms underlying repetitive behaviors to understand the relationship between various neural alterations resulting in autistic behavior. Next, in this study, we have conducted experiments utilizing mouse models of autism to investigate the role of cellular and network dysfunction in emergence of autistic behavior. We employed tract tracing approach to understand alterations in connectivity in CNTNAP2 knockout mouse model of autism displaying robust sociability deficit and repetitive behavior and in 129S1 inbred strain (DISC1 gene mutation) exhibiting core repetitive behavior and some of the co-morbid autistic behaviors such as anxiety. In addition, we also evaluated changes in inhibitory neurons and extracellular support structures, perineuronal nets in different cortical regions and at various postnatal ages in CNTNAP2 mutant mouse model. Utilizing CNTNAP2 knockout mouse model of autism, we analyzed effect of perineuronal nets removal in prefrontal cortex on behavior, resulting in rescuing of social interaction deficit in mutant mouse model of autism. Further, utilizing transgenic mouse model we elucidated the organization of insular corticothalamic connectivity. Utilizing 16p11.2 del mouse model of autism and 129S1 mice, we analyzed synaptic changes underlying behavioral alterations in autism. Together these studies suggest neuroanatomical, and physiological alterations resulting in emergence of ASD related behaviors.

Date

8-17-2022

Committee Chair

Lee, Charles C.

Available for download on Wednesday, August 15, 2029

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