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

Highlights

• MIA at specific development windows and brain regions induces ASD.

• MIA dysregulated ASD-related the non-chasm DEGs tend to disrupts fetal brain development.

• The coincidence window and non-chasm IRDEGs for conducting the mouse model to study the MIA-induced ASD.

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.

Introduction

The maternal immune activation (MIA) hypothesis has been implicated in neurodevelopment, which posits that environmental insults directed at maternal pregnancy can affect fetal neurodevelopment, thereby increasing vulnerability to autism spectrum disorders (ASDs) later in life [[1], [2], [3]]. MIA causes abnormal neuronal plasticity through processes such as excessive synaptic pruning and microglial activity, increasing the risk of ASDs [[4], [5], [6]]. ASD is defined by reactive changes in social interaction and communication increased repetitive and restricted behaviors repertoires and interests [7,8]. The etiology of ASD was caused by the complex interactions between genetic and environmental factors [9]. Despite recent studies have identified the significant overlap between transcriptome changes and genetic variants in MIA-exposed offspring and ASD individuals, there are still significant gaps in our knowledge regarding the exact mechanism of this process that MIA disrupts fetal brain development resulting in ASD [10]. Moreover, the pregnancy timing of exposure is also key in determining the phenotype and severity of the offspring [11,12]. The rising incidence of ASDs urgently needs to lessen the risk of this condition through pregnancy prevention strategies and novel postnatal therapies for mechanisms.

Considering the limitation in studying human fetal brain tissue since humans cannot be subject to invasive experimentation in clinical research, it is impossible to establish a causal relationship between MIA and increasing the risk of ASDs by relying on the examination of maternal blood, placenta and offspring brain, as well as epidemiological studies alone, making the animal research as an essential tool for understanding neurodevelopment and developing new diagnostic tools and therapeutics [11,13]. Several previous research in animal models of MIA, which have been conducted by lipopolysaccharide (LPS) and polyriboinosinic polyribocytidylic acid (poly(I:C)), have established causality by showing that MIA affect early neurodevelopment to induce the ASDs in offspring [2,[14], [15], [16]], as well as producing ASD-like behavioral and cognitive deficits [9,17,18]. Despite the numerous links between MIA disrupting early neurodevelopment during pregnancy and the risk of ASD in offspring by performing the animal models research, several key questions remain, such as when and where does MIA alter the transcript trajectory of normal brain development leading to ASD? Which human brain development window corresponds to the MIA specific windows? Whether the distinct neuropathological changes caused by MIA during specific development windows resemble the children and adults with ASD? Mice, as an important animal model, are different from humans in brain composition, developmental cycle and transcriptional landscape, resulting in drug therapy far from achieving the curative effect of radical cure [19,20]. As such, further investigation is necessary to seek the overlapping differentially expressed genes (DEGs; non-chasm) between MIA and ASD (including the human patients and mouse models) under the coincidence fetal developmental window. And how do these non-chasm DEGs disrupt the immune and metabolism pathways involved in this process?

In the present study, firstly, we proved that MIA was associated with ASD by comparing the DEGs obtained from the temporal transcriptome of MIA mouse and the ASD-associated risk genes from the public databases. Next, to determine the coincidence brain developmental windows between human and mice associated with MIA-induced ASDs in different brain regions, we employed Fisher's exact test to obtain the MIA-affected windows by comparing the MIA with four windows and human ASDs. Then these obtained windows were mapped into the normal mouse development to obtain the similar periods by comparing with the human fetal development. Due to a gap in transcriptome between before and long after birth, here we defined the concept of non-chasm DEGs, which were differentially expressed in the MIA mouse model and normal human development under the coincidence window, and stage (child or adult) of ASD human and mouse models. The enrichment analysis showed that immune- and metabolism-related function involved in this process. A large quantity of brain development-, immune-, and metabolism-related non-chasm DEGs obtained by screening the public database and relevant functions were overlapped in the ASD-related public databases. Our results support that MIA leading to abnormal embryonic neurodevelopment based on transcriptome induces the increasing risk of ASD in offspring. Thus, our study provides a bioinformatics analysis framework to understand the transcriptional abnormalities and neuropathology for how early-life inflammation induces ASD after birth.