Meta-Analysis of Brain Gene Expression Data from Mouse Model Studies of Maternal Immune Activation Using Poly(I:C)

Abstract

Maternal immune activation (MIA) is a known risk factor for schizophrenia (SCZ) and autism spectrum disorder (ASD) and is often modelled in animal studies in order to study the effect of prenatal infection on brain function including behaviour and gene expression. Although the effect of MIA on gene expression are highly heterogeneous, combining data from multiple gene expression studies in a robust method may shed light on the true underlying biological effects caused by MIA and this could inform studies of SCZ and ASD. This study combined four RNA-seq and microarray datasets in an overlap analysis and ranked meta-analysis in order to investigate genes, pathways and cell types dysregulated in the MIA mouse models. Genes linked to SCZ and ASD and crucial in neurodevelopmental processes including neural tube folding, regulation of cellular stress and neuronal/glial cell differentiation were among the most consistently dysregulated in these ranked analyses. Gene ontologies including K+ ion channel function, neuron and glial cell differentiation, synaptic structure, axonal outgrowth, cilia function and lipid metabolism were also strongly implicated. Single-cell analysis identified excitatory and inhibitory cell types in the cortex, hippocampus and striatum that may be affected by MIA and are also enriched for genes associated with SCZ, ASD and cognitive phenotypes. This points to the cellular location of molecular mechanisms that may be consistent between the MIA model and neurodevelopmental disease, improving our understanding of its utility to study prenatal infection as an environmental stressor.

Dual Role of the P2X7 Receptor in Dendritic Outgrowth during Physiological and Pathological Brain Development

“…Several epidemiological studies have indicated an association between maternal bacterial and viral infections (e.g., maternal influenza infection) during pregnancy and an increased incidence of schizophrenia in the offspring after puberty ( Shi et al, 2003 ; Meyer et al, 2005 ; Solek et al, 2018 ). A recent meta-analysis showed that the expression of genes linked to schizophrenia and other neurodevelopmental diseases is dysregulated in maternal immune activation (MIA) mouse models ( Laighneach et al, 2021 ). Recently, the potential of P2X7Rs as treatment targets for schizophrenia was examined.…”

An increase in Semaphorin 3A biases the axonal direction and induces an aberrant dendritic arborization in an in vitro model of human neural progenitor differentiation

“…Notably, recent evidences have underlined the potential critical role of Sema 3A in fostering these alterations [7,14,57]. An increasing number of epidemiological studies are stressing the significance of maternal inflammation in the onset of autism or schizophrenia [58][59][60][61]. In particular, prenatal exposure to infections have been described as causative factor in rise of schizophrenic births [62].…”

“…An increasing number of epidemiological studies are stressing the significance of maternal inflammation in the onset of autism or schizophrenia [ 58 – 61 ]. In particular, prenatal exposure to infections have been described as causative factor in rise of schizophrenic births [ 62 ].…”

Transcriptomic profiling of the developing brain revealed cell-type and brain-region specificity in a mouse model of prenatal stress

“…Besides direct impacts on the fetal brain, transcriptomic alterations in adult brain after prenatal exposure of adverse events were reported in animal studies. For example, transcriptomic profiling on adult cortex [46,49,50], amygdala [51], and nucleus accumbens [50] in the animal model of maternal immune activation (MIA) identified many gene pathways critical for neurodevelopmental processes, including important genes associated with schizophrenia (SCZ), autism spectrum disorder (ASD) and cognitive phenotypes [52].…”