title: Investigating the effect of environmental risk factors for neuropsychiatric and neurodevelopmental disorders on gene expression in brain tissue from mouse models
Creators: name: Laighneach, Aodán
Publisher: name: University of Galway
Year: 2024
Subjects: subject: Mouse models
subject: Schizophrenia
subject: Gene expression
subject: Social isolation
subject: Maternal immune activation
subject: Neurodevelopmental disorder
subject: Natural Sciences
subject: Chemistry
subject: Biochemistry

description: Exposure to certain environmental stressors before birth or in early life increases risk for neuropsychiatric and neurodevelopmental disorders. These stressors include the prenatal factor of maternal immune activation (MIA) and the early life factor of social isolation (SI). The underlying molecular biology of these factors cannot be actively studied in humans and thus, animals models such as the mouse provide a crucial alternative. Here, using previously published data for MIA (Chapter 2) and newly generated RNA-seq data for SI (Chapter 3), I use mouse models to investigate how gene expression in the brain is impacted by these environmental risk factors. Furthermore, I assess the effects of a non-steroidal anti-inflammatory drug, Celecoxib (CEL) on SI-induced gene expression changes (Chapter 4). The neurobiological relevance of gene expression changes and possible links to established genetic risk for human neuropsychiatric and neurodevelopmental disorders are also investigated. Based on reanalysis of published data, MIA induces highly variable gene expression changes in the mouse brain. The most consistently dysregulated genes however, based on ranking by individuals p-values, had functions related to neural tube folding, regulation of cellular stress, neuronal/glial cell differentiation and some genes were directly associated with neuropsychiatric disorders such as Fgf10 and Cck. Furthermore, cell type enrichment analysis linked genes consistently dysregulated by MIA and common genetic risk for schizophrenia (SCZ) and cognitive ability (IQ). The SI factor, investigated initially in Chapter 3, induced differentially-expressed genes (DEGs) in male and female mouse hippocampus. These DEGS are shown to impact the structure and function of synapse biology, show enrichment for common SNP heritability for SCZ and bipolar disorder (BPD) in males and females as well as for cognitive ability in females. Likewise, DEGs in males are enriched for genes harbouring rare de novo mutations contributing to autism spectrum disorder. Finally, marker genes for hippocampal astrocytes were enriched in females DEGs. The final study (Chapter 4) reinvestigated the SI factor in females, however with the addition of a new region (amygdala) and new factor (CEL). A number of commonalities persisted in the nominally-significant SI-induced DEGs, most notably the implication of cell types with roles in the blood-brain barrier (BBB). When investigated alone, CEL administration had a strong effect on gene expression in the hippocampus, but not amygdala. Consequently, when investigating nominally-significant gene expression changes induced by CEL and SI in combination, CEL appeared to reduce the proportion of DEGs relating to synapse biology in the hippocampus compared to SI alone. This was not found to be the case in the amygdala. The results from this thesis provide an insight into how environmental stressors affect gene expression in the mouse brain. Gene expression changes related to both synapse and glial cell biology. Regions encapsulating genes dysregulated by these factors often overrepresent human genetic variation contributing to neuropsychiatric disorders and cognition. These data generally support the molecular validity of environmental animal models of neuropsychiatric and neurodevelopmental disorder, while also highlighting challenges and limitations associated with their use.