Abstract
In utero exposure to maternal immune activation (MIA) is an environmental risk factor for neurodevelopmental and neuropsychiatric disorders. Animal models provide an opportunity to identify mechanisms driving neuropathology associated with MIA. We performed time-course transcriptional profiling of mouse cortical development following induced MIA via poly(I:C) injection at E12.5. MIA-driven transcriptional changes were validated via protein analysis, and parallel perturbations to cortical neuroanatomy were identified via imaging. MIA-induced acute upregulation of genes associated with hypoxia, immune signaling, and angiogenesis, by 6 hr following exposure. This acute response was followed by changes in proliferation, neuronal and glial specification, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cells in germinal zones and alterations in neuronal and glial populations were identified in the MIA-exposed cortex. Overall, paired transcriptomic and neuroanatomical characterization revealed a sequence of perturbations to corticogenesis driven by mid-gestational MIA.
Highlights
Epidemiological association between maternal infection and neurodevelopmental disorders (NDDs) has been found for autism spectrum disorder (ASD), schizophrenia (SZ), bipolar disorder (BPD), anxiety, and major depressive disorder (MDD) (Brown, 2011; Estes and McAllister, 2015; Parboosing et al, 2013; Patterson, 2009)
We used a strategy of first defining differential expression (DE) genes at each time-point using the general linear model (GLM) approach implemented in edgeR, followed by mapping DE signatures to systems-level expression patterns via module assignment using weighted gene co-expression network analysis (WGCNA)
Studies leveraging maternal immune activation (MIA) models in mice have demonstrated the role of maternal immune signaling as a risk factor for cellular, anatomical, and behavioral outcomes in offspring
Summary
Epidemiological association between maternal infection and neurodevelopmental disorders (NDDs) has been found for autism spectrum disorder (ASD), schizophrenia (SZ), bipolar disorder (BPD), anxiety, and major depressive disorder (MDD) (Brown, 2011; Estes and McAllister, 2015; Parboosing et al, 2013; Patterson, 2009). Maternal immune activation (MIA) itself is sufficient to produce NDD-relevant outcomes in offspring in animal models (Canetta et al, 2014; Machado et al, 2015). Recent studies have identified acute transcriptomic changes in fetal brain in mice and rats at single time-points (3–4 hr) following MIA, with significant overlap between transcriptome changes in the cortices of MIA-exposed offspring and those altered in the brains of children with ASD (Lombardo et al, 2018). We combined time-course transcriptomics with neuroanatomy to map changes in prenatal mouse cortical development following MIA induced by poly(I:C) injection at E12.5
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