Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the most common heritable single gene cause of Autism Spectrum Disorder (ASD). The Fragile X (FMR1-KO) mouse model has been used to understand the pathophysiology of the disease. However, the majority of studies have been done in adult mice and early life outcomes have yet to be explored. Therefore, in order to contribute to the knowledge of the neurodevelopmental processes associated with brain disorders, this thesis examines postnatal outcomes in the Fragile X Mouse Model: early life behaviours, the developmental trajectory of a set of ASD risk genes, and neuroanatomical phenotype. The first study examined ultrasonic vocalizations in pups and showed a transient increase in calls in FMR1-KO mice. To understand the relationship between early life behaviours, the second study examined outcomes in the pre-pubertal period in these mice when challenged with lipopolysaccharide and maternal separation. The results showed genotype and treatment interactions affecting sexually dimorphic behavioural outcomes and developmental milestones. In the third study, possible underpinnings of behavioural differences were explored by examining mRNA expression of the neuroligins and neurexins. In FMR1-KO mice, changes were transient and sex-specific, suggesting these as molecular effectors in the disease. Lastly, using structural brain imaging, the fourth study examined regional volume differences that may be related to behavioural differences. Differences in regions affected in FXS patients were observed and genetic background was shown to affect the neuroanatomical phenotype. Overall, this thesis demonstrates that the FXS model recapitulates some outcomes in other ASD mouse models and shows that this single gene has multiple interactions with sex, strain, and postnatal challenge which manifests at specific ages at molecular, brain structure and behavioural levels. This work contributes to the efforts elucidating the neurobiology of ASD and reverse translation approaches to identify therapeutic targets for neurodevelopment disorders. / Dissertation / Doctor of Philosophy (PhD) / Autism spectrum disorder (ASD) is a diagnosis based on observed behaviours: impaired communication and repetitive actions. However, there are genetic and other behavioural differences in ASD patients that are not shared among the group. It is important to tease apart this group since current treatments for ASD do not target the biological problems or the core impairments. This thesis focuses on Fragile X Syndrome, the leading genetic condition that results in ASD in order to understand the biological basis of ASD. Using a mouse model, compared to healthy mice, these studies report changes in behaviours, in the size of different brain regions, and in molecules involved in connecting brain cells during development. These findings shed light on the molecular story underlying ASD. By understanding the nature of influences on the developing brain, the type and timing of interventions can be designed to keep the brain on a healthy trajectory.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/17209 |
| Date | 06 1900 |
| Creators | Lai, Jonathan |
| Contributors | Foster, Jane, Neuroscience |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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