Dynamic changes in spatiotemporal transcriptome reveal maternal immune dysregulation of autism spectrum disorder

Abstract

Maternal immune activation (MIA) during pregnancy is known to be an environmental risk factor for neurodevelopment and autism spectrum disorder (ASD). However, it is unclear at which fetal brain developmental windows and regions MIA induces ASD-related neurodevelopmental transcriptional abnormalities. The non-chasm differentially expressed genes (DEGs) involved in MIA inducing ASD during fetal brain developmental windows were identified by performing the differential expression analysis and comparing the common DEGs among MIA at four different gestational development windows, ASD with multiple brain regions from human patients and mouse models, and human and mouse embryonic brain developmental trajectory. The gene set and functional enrichment analyses were performing to identify MIA dysregulated ASD-related the fetal neurodevelopmental windows and brain regions and function annotations. Additionally, the networks were constructed using Cytoscape for visualization. MIA at E12.5 and E14.5 increased the risk of distinct brain regions for ASD. MIA-driven transcriptional alterations of non-chasm DEGs, during the coincidence brain developmental windows between human and mice, involving ASD-relevant synaptic components, as well as immune- and metabolism-related functions and pathways. Furthermore, a great number of non-chasm brain development-, immune-, and metabolism-related DEGs were overlapped in at least two existing ASD-associated databases, suggesting that the others could be considered as the candidate targets to construct the model mice for explaining the pathological changes of ASD when environmental factors (MIA) and gene mutation effects co-occur. Overall, our search supported that transcriptome-based MIA dysregulated the brain development-, immune-, and metabolism-related non-chasm DEGs at specific embryonic brain developmental window and region, leading to abnormal embryonic neurodevelopment, to induce the increasing risk of ASD.