Date of Completion

7-25-2014

Embargo Period

7-24-2016

Keywords

Dcdc2, Cntnap2, BXD29-Tlr4lps-2J/J

Major Advisor

R. Holly Fitch

Associate Advisor

Joseph LoTurco

Associate Advisor

Glenn Rosen

Associate Advisor

Rahul Kanadia

Associate Advisor

Etan Markus

Field of Study

Psychology

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The development of the brain is an immensely complicated process that is highly regulated by numerous genetic pathways. Disruption within any stage of this operation—from proliferation, to neuronal migration, to synaptogenesis—could ultimately lead to deleterious behavioral outcomes, ranging from severe intellectual disability and gross motor developmental delays to more subtle cognitive impairments such as language disability. It is therefore no surprise that neuroanatomical anomalies resulting from of altered cortical development are associated with a number of language related neurodevelopmental disorders such as specific language impairment (SLI), dyslexia, and autism spectrum disorders (ASD). Over the past decade, genetic association studies have identified numerous genetic variants that are more commonly observed in language and reading impaired populations. However, these studies cannot ascertain whether these genes are central to the etiology of the disorder (since association but not causatlity is repoterd). As another approach, rodent models have provided an invaluable tool to elucidate functional gene-brain-behavior relationships that are nearly impossible to examine clinically. Indeed, rodent models in the past have been successful in linking clinically relevant neuropathological changes associated with language disability to poor behavioral outcomes in the domains of auditory processing and cognitive performance on water maze tasks—behaviors that have been shown to be deficient in language and reading impaired populations. Given the pressing need to understand how genetics underlie the development of language dysfunction, the series of studies presented in this thesis was designed to examine and characterize neurobehavioral, neuroanatomic, and genetic profiles of language and reading related disorders in rodents, specifically using recombinant inbred and transgenic strains of mice. In these experiments, we defined relationships between: 1) key behavioral phenotypes associated with language dysfunction and social communication/interaction; 2) disruption of neuronal migration; 3) changes in subcortical anatomy along the central auditory pathway; and 4) sex differences across these factors. From these relationships, our goal was to identify how promising risk genes identified from clinical populations (e.g., DCDC2 (dyslexia) and CNTNAP2 (SLI and ASD)) as well as associated neuroanatomical anomalies of neuronal migration, may collectively mediate the constellation of language-related and cognitive dysfunctions observed in relevant clinical populations.

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