Pervasive developmental disorders are a group of neurodevelopmental-neuropsychiatric disorders that are characterized by variable and severe pervasive impairments in several areas of child development, notably social interaction, communication and imagination. They all share clinical features but differ in the severity and age of onset of the impairments. Except for Rett Syndrome (RTT), the etiology of these disorders is unknown, but there is strong evidence that genetic factors contribute to their pathogenesis. While no major genes have been linked to theses disorders linkages, association and chromosomal studies suggest that many loci may be involved. / One aim of the present study was to search for genetics variants associated with autism and other related disorders. This study represents the first family-based association study looking at the entire X chromosome using a French-Canadian autistic population, a genetically homogenous group. We found association between autism and markers at two loci. Our results support the existence of a putative gene located on the X chromosome and moreover the founder effect, in the French-Canadian population, may provide greater power to fine map disease genes especially in complex traits. / The second aim of the present thesis was to confirm the involvement of the MECP2 gene in our RTT group of patients. While we confirm the presence of mutations in this gene in our cohort of RTT patients we also demonstrated that clinical stringency greatly influences the mutation detection rate for this disorder.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Sept. 16, 2008). Includes bibliographical references.

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Although the central nervous system was long perceived as the ivory tower without immune entities, there is growing evidence that the immune and nervous systems are intimated connected. These two systems have been shown to communicate both cellularly and molecularly under physiological and pathological conditions. Despite our increasing understanding of the interplay between these two systems, there are still numerous open questions. In this thesis, I address such unanswered questions related to: the role of microglia and their mechanism in contributing to pathologies in Rett syndrome; the beneficial effects of T-cell secreted cytokines in supporting social brain function; the evolutionary link of the interactions between the nervous and immune systems; the transcription regulation of a subset of microglia population in common neurodegenerative diseases. Collectively, the current thesis is focused on the joint frontier of bioinformatics and experimental work in neuroimmunology. A multifaceted approach, that includes transcriptomics, genomics and other biomolecular modules, was implemented to unearth signaling pathways and mechanisms underlying the presenting biological phenomena. The findings of this thesis can be summarized as follows: 1) MeCP2 acts as a master regulator in the transcriptional repression of inflammatory stimuli in macrophages; 2) T-cell secreted IFN-γ supports social brain function through an evolutionally conserved interaction between the immune and nervous systems; 3) The APOE-TREM2 pathway regulates the microglia phenotype switch in neurodegenerative diseases. Provided that recent technologies allow for readily manipulating the immune system, the findings presented herein may create new vistas for therapeutic interventions in various neurological disorders.

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In this study we tested whether the prevalence or synaptic distribution of NMDA receptor subunits would be altered in the brain of the MeCP2-null mouse model of Rett syndrome. Detergent resistant membranes (DRMs) and post-synaptic densities (PSDs) were isolated from the synaptic membranes treated with TritonX-100, and resolved by sucrose density gradient centrifugation. Immunoblot analysis of the resulting density gradient fractions revealed that the relative distribution of the different NMDA receptor subunits between the DRM fractions, soluble fractions, and insoluble postsynaptic density fractions was preserved in the MeCP2-null brain. However, analysis of the overall NMDA receptor subunit prevalence within these fractions revealed a significant decrease in the expression of the NR1 and NR2A subunits, but not the NR2B subunit, in the MeCP2-null brain. The preservation of distribution of NMDAR subunits to the synaptic membranes, together with the decrease in NR1 and NR2A prevalence, suggest an imbalance in equilibrium between the mature and the immature synapses in a mouse model of Rett syndrome.

Mutations in the X-linked gene encoding Methyl-CpG-binding protein 2 (MECP2) cause the neurodevelopmental disorder Rett syndrome, a common genetic cause of mental retardation in females. Although alterations in performance of MeCP2-deficient mice in specific behavioural tasks have been documented, it remains unclear if, and to what degree, MeCP2 dysfunction affects patterns of periodic behavioural and electroencephalographic activity. To address this, we monitored daily rhythmic patterns of core body temperature, gross motor activity, and cortical delta power from MeCP2-deficient mice and correlated it against regional MeCP2 expression levels. Our results show that normal daily rhythmic behavioural patterning of delta wave activity, body temperature and mobility are disrupted in these mice. Moreover, MeCP2-deficient mice displayed lower average core body temperature and significantly greater body temperature fluctuation than wild-type female mice. Finally, we also found that epileptiform discharge activity in MeCP2-deficient mice is more predominant during times of behavioural activity compared to inactivity.

In this study we tested whether the prevalence or synaptic distribution of NMDA receptor subunits would be altered in the brain of the MeCP2-null mouse model of Rett syndrome. Detergent resistant membranes (DRMs) and post-synaptic densities (PSDs) were isolated from the synaptic membranes treated with TritonX-100, and resolved by sucrose density gradient centrifugation. Immunoblot analysis of the resulting density gradient fractions revealed that the relative distribution of the different NMDA receptor subunits between the DRM fractions, soluble fractions, and insoluble postsynaptic density fractions was preserved in the MeCP2-null brain. However, analysis of the overall NMDA receptor subunit prevalence within these fractions revealed a significant decrease in the expression of the NR1 and NR2A subunits, but not the NR2B subunit, in the MeCP2-null brain. The preservation of distribution of NMDAR subunits to the synaptic membranes, together with the decrease in NR1 and NR2A prevalence, suggest an imbalance in equilibrium between the mature and the immature synapses in a mouse model of Rett syndrome.

Mutations in the X-linked gene encoding Methyl-CpG-binding protein 2 (MECP2) cause the neurodevelopmental disorder Rett syndrome, a common genetic cause of mental retardation in females. Although alterations in performance of MeCP2-deficient mice in specific behavioural tasks have been documented, it remains unclear if, and to what degree, MeCP2 dysfunction affects patterns of periodic behavioural and electroencephalographic activity. To address this, we monitored daily rhythmic patterns of core body temperature, gross motor activity, and cortical delta power from MeCP2-deficient mice and correlated it against regional MeCP2 expression levels. Our results show that normal daily rhythmic behavioural patterning of delta wave activity, body temperature and mobility are disrupted in these mice. Moreover, MeCP2-deficient mice displayed lower average core body temperature and significantly greater body temperature fluctuation than wild-type female mice. Finally, we also found that epileptiform discharge activity in MeCP2-deficient mice is more predominant during times of behavioural activity compared to inactivity.