Individuals with autism spectrum disorders (ASDs) are impaired in cognitive processes and emotional regulation, and exhibit stereotyped behaviours. Dopamine (DA) modulates executive functions, learning, memory, emotional processing and social cognition; all of which are impaired in individuals with ASDs. Because DA modulates a number of processes that are impaired in individuals with ASDs, genes in the dopaminergic pathway are good candidates for genes influencing autistic behaviours. As our previous findings suggested a role for a dopamine-related gene in families with only affected males, this thesis describes a comprehensive study of five genes affecting DA synthesis, levels and function in mothers and affected males with ASDs in an initial TEST cohort of 112 male-only affected sib-pair families as well as a replication study in three additional male-only family cohorts. I genotyped three to five polymorphisms in the TH, SLC6A3, DRD1, DRD2 and PPP1R1B genes and performed population-based single marker case-control comparisons, family-based association tests, quantitative transmission disequilibrium tests as well as haplotype-based analyses and tests for gene-gene interactions. I found evidence for association of the DRD1 (P=0.0027-0.040), DRD2 (P=0.0002-0.007) and PPP1R1B (P=0.00042-0.001) genes with autism in affected males from the TEST cohort. Evidence for DA-related gene interactions were found between polymorphisms in DRD1, DRD2 and PPP1R1B (P=0.0094-0.012) in affected males relative to a comparison group. Furthermore, I found that polymorphisms in the TH and DRD1 genes were associated with the risk for mothers having sons with ASD in the TEST families (P=0.007-0.025) and putative risk alleles in DRD1 and DRD2 were preferentially transmitted from mothers (P=0.016) and fathers (P=0.023) respectively, to affected children. All findings remained significant following corrections for multiple testing. The TEST cohort findings were not replicated in other family cohorts. However, an examination of dysmorphology data for the different family sets revealed phenotypic differences and thus, genetic differences are to be expected. In summary, I found evidence for a contribution of DA-related genes in a specific family cohort with ASDs. Additional functional and phenotypic studies will enable a better understanding of the contributions and implications of these findings to our understanding of autism. / Thesis (Ph.D, Physiology) -- Queen's University, 2009-03-18 13:58:12.223

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Developmental ethanol exposure causes both structural and functional changes in the brain that can result in cognitive and behavioral abnormalities. The hippocampal formation, an area of the brain strongly linked with learning and memory, is particularly vulnerable to the teratogenic effects of ethanol. Research in this thesis focused on uncovering the effects of developmental ethanol exposure on hippocampal function in adulthood, particularly synaptic plasticity (a putative neurobiological mechanism of learning and memory). The first experiment sought to determine the temporal vulnerability of hippocampal synaptic plasticity as a function of exposure to ethanol during a single trimester. Ethanol exposure during the 1st or 3rd trimester equivalent resulted in minor changes in synaptic plasticity in adult offspring. In contrast, ethanol exposure during the 2nd trimester equivalent resulted in a pronounced decrease in long-term potentiation (LTP), indicating that the timing of exposure determines the severity of the deficit. The second experiment was aimed at determining the effects of prenatal ethanol exposure (1st and 2nd trimester equivalent combined) on bidirectional synaptic plasticity. Prenatal ethanol exposure resulted in a profound reduction in LTP but did not affect long-term depression. These findings show that prenatal ethanol exposure creates an imbalance in bidirectional synaptic plasticity. The third experiment sought to determine if prenatal ethanol exposure alters the affect of acute ethanol exposure in adulthood on synaptic plasticity. Acute exposure to ethanol in adulthood attenuated LTP in control offspring. Conversely, the magnitude of LTP was not affected by acute ethanol application in prenatal ethanol offspring. These results suggest that prenatal ethanol exposure alters the physiological response to ethanol in adulthood. Together, the results from the experiments undertaken in this thesis demonstrate long-lasting alterations in synaptic plasticity as the result of developmental ethanol exposure. Furthermore, these results allude to a malfunction of neural circuits within the hippocampal formation, perhaps relating to the learning and memory deficits observed in individuals with fetal alcohol spectrum disorders. / Graduate

Doctor of Philosophy / This study defines Theory-of-Mind as the ability to experience one’s own mind and understand the minds of others to the extent necessary to make sense of human behaviour and the world. Since the concept of Theory-of-Mind was first applied to people with ASD (Baron-Cohen, Leslie & Frith, 1985), lack of Theory-of-Mind has been used to explain their cognitive difficulties (National Research Council, 2003), along with social, communicative and imaginative impairments (Frith, Happé & Siddons, 1994). Previous studies have tended to think of Theory-of-Mind in terms of a simple binary of deficit or credit; to exclude the voices of people with ASD; to emphasise the cognitive aspects of Theory-of-Mind over its affective aspects; and to emphasise understanding the minds of others over experiencing one’s own mind. This study aims to address these issues by investigating Theory-of-Mind as subjectively experienced by students with ASD and objectively understood by their teachers. It is the first attempt in the study of Theory-of-Mind to include the voices of individuals with ASD along with the professional views of their teachers. This study takes an interdisciplinary approach, supported by philosophy of mind and special education. A grounded theory approach and a mixed methods research design combine to build and strengthen a theory of Theory-of-Mind. For Theory-of-Mind as subjectively experienced, 20 senior secondary and post secondary school students with ASD from Republic of Korea were interviewed and student-produced documents were reviewed to draw out their inner experiences. The Korean Wechsler Adult Intelligence Scale and the Korean Vineland Social Maturity Scale were employed to assess IQ and social competence. For Theory-of-Mind as objectively understood, their teachers’ beliefs regarding their students with ASD were sought through in-depth interviews, a review of teacher-produced documents and administration of a newly developed Teacher Questionnaire. This study reports differences between Theory-of-Mind as subjectively experienced and objectively observed, and variations within the components of Theory-of-Mind. The role of imagination in Theory-of-Mind and the relationships between Theory-of-Mind components, IQ and social competence are discussed. As a result, a Theory-of-Mind continuum model and Theory-of-Mind Typology is proposed.

Doctor of Philosophy / This study defines Theory-of-Mind as the ability to experience one’s own mind and understand the minds of others to the extent necessary to make sense of human behaviour and the world. Since the concept of Theory-of-Mind was first applied to people with ASD (Baron-Cohen, Leslie & Frith, 1985), lack of Theory-of-Mind has been used to explain their cognitive difficulties (National Research Council, 2003), along with social, communicative and imaginative impairments (Frith, Happé & Siddons, 1994). Previous studies have tended to think of Theory-of-Mind in terms of a simple binary of deficit or credit; to exclude the voices of people with ASD; to emphasise the cognitive aspects of Theory-of-Mind over its affective aspects; and to emphasise understanding the minds of others over experiencing one’s own mind. This study aims to address these issues by investigating Theory-of-Mind as subjectively experienced by students with ASD and objectively understood by their teachers. It is the first attempt in the study of Theory-of-Mind to include the voices of individuals with ASD along with the professional views of their teachers. This study takes an interdisciplinary approach, supported by philosophy of mind and special education. A grounded theory approach and a mixed methods research design combine to build and strengthen a theory of Theory-of-Mind. For Theory-of-Mind as subjectively experienced, 20 senior secondary and post secondary school students with ASD from Republic of Korea were interviewed and student-produced documents were reviewed to draw out their inner experiences. The Korean Wechsler Adult Intelligence Scale and the Korean Vineland Social Maturity Scale were employed to assess IQ and social competence. For Theory-of-Mind as objectively understood, their teachers’ beliefs regarding their students with ASD were sought through in-depth interviews, a review of teacher-produced documents and administration of a newly developed Teacher Questionnaire. This study reports differences between Theory-of-Mind as subjectively experienced and objectively observed, and variations within the components of Theory-of-Mind. The role of imagination in Theory-of-Mind and the relationships between Theory-of-Mind components, IQ and social competence are discussed. As a result, a Theory-of-Mind continuum model and Theory-of-Mind Typology is proposed.

Thesis (Ph. D.)--Auburn University. / Abstract. Includes bibliographical references (p. 80-87).

Thesis (Ph. D.)--West Virginia University, 2009. / Title from document title page. Document formatted into pages; contains xii, 170 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 93-112).

Title from title page (viewed April 28, 2010) Bouvé College of Health Sciences. Dept. of Counseling and Applied Educational Psychology. Includes bibliographical references (p. 167-176).

Les TSA représentent un groupe de troubles neurodéveloppementaux défini par des déficits des interactions sociales, de la communication et des comportements restreints et répétitifs. A ce jour le diagnostic de l’autisme se fait uniquement sur la base de symptômes cliniques. Il n’existe aucun biomarqueur des TSA. Ce travail s’inscrit donc (1) dans la recherche de biomarqueurs prédictifs dans les TSA et (2) dans la mise en évidence des dysfonctions métaboliques cérébrales dans un modèle de rat (rat valproate, VPA). Pour mettre en évidence des biomarqueurs urinaires prédictifs nous avons analysé simultanément les données issues de plusieurs technologies analytiques afin d’améliorer la robustesse et la capacité prédictive des modèles statistiques. L’autre partie de la thèse consistait à caractériser et à comparer au cours du développement l’évolution du métabolome du rat VPA. Nous avons mis en évidence des perturbations des voies de la neurotransmission, énergétique, du stress oxydatif etc. Même si on ne peut pas transposer les résultats obtenus chez le rat, à l’homme, le modèle VPA permet néanmoins de mieux comprendre les perturbations physiologiques cérébrales induites par ce médicament. / ASDs are a group of neurodevelopmental disorders defined by deficits in social interaction, communication and restricted and repetitive behaviors. To date, the diagnosis of autism is made only on the basis of clinical symptoms. There is no biomarker of ASD. The aim of this work is (1) the search of predictive biomarkers in ASD and (2) the better understanding of brain metabolic dysfunctions in a rat model (valproate rat, VPA). To highlight urinary predictive biomarkers we analyzed together data from different analytical technologies in order to improve the robustness and predictive power of statistical models. The second part of the thesis was to characterize and compare the cerebral metabolome of VPA rat during development. We showed disturbances of neurotransmission, energy, oxidative stress pathways. Even if results obtained in rats cannot be transposed to humans, the VPA model still allows a better understanding the brain physiological disturbances induced by the drug.