Genome-Wide Transcriptional Profiling and Structural Magnetic Resonance Imaging in the Maternal Immune Activation Model of Neurodevelopmental Disorders

Abstract

Prenatal exposure to maternal infection increases the risk of neurodevelopmental disorders, including schizophrenia and autism. The molecular processes underlying this pathological association, however, are only partially understood. Here, we combined unbiased genome-wide transcriptional profiling with follow-up epigenetic analyses and structural magnetic resonance imaging to explore convergent molecular and neuromorphological alterations in corticostriatal areas of adult offspring exposed to prenatal immune activation. Genome-wide transcriptional profiling revealed that prenatal immune activation caused a differential expression of 116 and 251 genes in the medial prefrontal cortex and nucleus accumbens, respectively. A large part of genes that were commonly affected in both brain areas were related to myelin functionality and stability. Subsequent epigenetic analyses indicated that altered DNA methylation of promoter regions might contribute to the differential expression of myelin-related genes. Quantitative relaxometry comparing T 1 , T 2 , and myelin water fraction revealed sparse increases in T 1 relaxation times and consistent reductions in T 2 relaxation times. Together, our multisystem approach demonstrates that prenatal viral-like immune activation causes myelin-related transcriptional and epigenetic changes in corticostriatal areas. Even though these abnormalities do not seem to be associated with overt white © The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Downloaded from https://academic.oup.com/cercor/article-abstract/27/6/3397/2333950 by University of Zurich user on 23 November 2017 matter reduction, they may provide a molecular mechanism whereby prenatal infection can impair myelin functionality and stability.

Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation

“…Housekeeper controls (β-actin, Tata-binding protein, ubiquitin-C mRNAs) and the geomean of all three did not differ according to diagnosis (all t < 0.74, df = 55, p > 0.05) in the human cohort [25]. In the MIA model, ribosomal phosphoprotein (36B4) was used as the housekeeper control as validated previously [47,49]. 36B4 expression was unaffected by MIA (t < 0.65, df = 62, p > 0.05).…”

“…GD17 in the mouse roughly corresponds to human gestational weeks 13-14 in terms of midbrain development (http://translatingtime.org/translate). It was selected because of our previous immunohistochemical and imaging studies showing dopamine-related cellular and volumetric changes in the ventral midbrain of adult Smoker at time of death (yes/no/unknown) 11/12/6 16/6/6 -offspring exposed to MIA at GD17 [46,47]. Poly(I:C) (5 mg/kg) was dissolved in 0.9% NaCl (vehicle) and was administered intravenously into the tail vein (final concentration, 1 mg/ml).…”

“…Mouse substantia nigra RNA was extracted using RNeasy Plus Universal Mini Kits (Qiagen, Hilden, Germany) according to manufacturer's instruction. Quantitative PCR was conducted with iScript one-step RT-PCR kits and a Taqman real-time system (CFX384, Bio-Rad Laboratories, Cressier, Switzerland) as previously [47,49].…”

“…36B4 expression was unaffected by MIA (t < 0.65, df = 62, p > 0.05). Relative gene expression was calculated with the 2 −ΔΔCt method [50], normalizing to 36B4 (mouse) [47,49] or housekeeper Ct geomean (human) [51]. Gene expression data are presented as fold change of relative mRNA levels ± SEM.…”

Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects

“…We (Matrisciano et al, 2013; Dong et al, 2016; Labouesse et al, 2015), and others (Richetto et al, 2016) have shown that behavioral (social interaction deficits, fear conditioning, anxiety, stereotype behavior) and molecular (methylation related epigenetic modifications at GABAeric genes), endophenotypes similar to the behavioral and molecular endophenotypes present in ASD patients, were found to be present in mice exposed in utero to stress, infection, toxins, or drugs that interfere with chromatin remodeling. In addition, in these mice, similar to ASD patients, there is increased binding of MECP2 to the GAD1 and RELN promoters and reduced expression of the corresponding mRNAs.…”