Investigating the effect of environmental risk factors for neuropsychiatric and neurodevelopmental disorders on gene expression in brain tissue from mouse models

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 ...