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

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.

Prenatal Maternal Infections and Children’s Neurodevelopment in the UK Millennium Cohort Study: A Focus on ASD and ADHD

Objective: No clear answer has yet been attained as to the influence of prenatal exposure to infection on autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), either alone or as co-occurring issues. The current study examined links between hospital-recorded and maternal-reported prenatal infections and ASD, ADHD, and co-occurring ASD and ADHD. Methods: Participants were n = 15,462 children and mother pairs from the Millennium Cohort Study (MCS), a population-representative UK sample. Results: Findings show associations between maternal-reported infections and ASD, and some evidence of links with ADHD and co-occurring ASD and ADHD. Hospital-recorded infections were not found to be associated with ASD, ADHD, or their co-occurrence. Agreement between hospital-recorded and maternal-reported infections was low, which may explain the discrepant findings. Conclusion: Prenatal maternal infections may be associated with increased odds of ASD and ADHD. Findings point to the importance of drawing on multiple sources of information when ascertaining prenatal infection status.

A Proof-of-Concept Study of Maternal Immune Activation Mediated Induction of Toll-Like Receptor (TLR) and Inflammasome Pathways Leading To Neuroprogressive Changes and Schizophrenia-Like Behaviors in Offspring.

Infection, particularly prenatal infection leads to an enhanced risk of schizophrenia in the offspring. Interestingly, few data exist on the pathway(s) such as TLR and inflammasome, primarily involved in sensing the microorganisms and inducing downstream inflammatory responses, apoptosis and neuroprogressive changes in the prenatal infection-induced risk of schizophrenia. Herein, we aimed to discern whether prenatal infection-induced maternal immune activation (MIA) causes schizophrenia-like behaviors through activation of TLR and inflammasome pathways in the brain of offspring. Sprague Dawley rats (n=15/group) were injected either with poly (I:C) or LPS or saline at gestational day (GD)-12. Significantly elevated plasma levels of IL-1β, IL-6, TNF-α and IL-17A assessed after 24 hours were observed in poly (I:C) and LPS-treated rats, indicating MIA. The offspring rats of poly (I:C)-and LPS-treated dams displayed increased anxiety-like behaviors, deficits in social behaviors and prepulse inhibition. The hippocampus of offspring rats showed increased expression of TLR3, TLR4, NLRP3, IL-1β, and IL-18 of poly (I:C) and TLR3, TLR4, NLRP3, Cas1, IL-1β, and IL-18 of LPS-treated dams. Notably, the expression of these genes showed a positive correlation with apoptotic and a negative correlation with neuroprotective genes. Furthermore, TLR and inflammasome genes had significant impact on social deficits and impaired prepulse inhibition in offspring rats. The results suggest MIA due to prenatal infection perhaps trigger TLR, inflammasome and apoptotic pathways leading to the induction of schizophrenia-like behaviors in the later stages of life. Prenatal infections seem to drive neuroprogression and subsequently schizophrenia-like symptoms through a common central pathway involving TLR, inflammasome and apoptosis.

Amniotic band syndrome with double encephalocele: A case report

Background: Amniotic band syndrome (ABS) is a rare condition of controversial etiology that is associated with varying degrees of anomalies. This study reports a case of a newborn with ABS associated with double encephalocele in the frontal region. Case Description: A 29-year-old primiparous woman with no history of prenatal infection or consanguineous marriage had a cesarean section at gestational week 38, giving birth to a newborn who was well but had limb anomalies (constriction rings, amputations, and syndactyly) and craniofacial anomalies, mainly double frontal encephalocele. The patient underwent surgical repair and subsequent placement of a ventriculoperitoneal shunt. Conclusion: Studies clarifying this uncommon association with double encephalocele are limited. ABS associated with double encephalocele is rare and even more complex when associated with other anomalies. Thus, the conditions in such children are severe and require multidisciplinary monitoring.

High transmissibility and fetal pathogenicity of recent Zika virus strains from the African lineage

SummaryThe global emergence of Zika virus (ZIKV) in the last decade revealed the unprecedented ability for a mosquito-borne virus to cause congenital birth defects such as microcephaly. A puzzling aspect of ZIKV emergence is that all human outbreaks and birth defects to date have been exclusively associated with the Asian ZIKV lineage, despite a growing body of laboratory evidence pointing towards higher transmissibility and pathogenicity of the African ZIKV lineage. Whether this apparent paradox reflects the use of relatively old African ZIKV strains in most laboratory studies is unclear. Here, we experimentally compared the transmissibility and pathogenicity of seven low-passage ZIKV strains representing the recently circulating viral genetic diversity. We found that recent African ZIKV strains largely outperformed their Asian counterparts in mosquito transmission kinetics experiments, which translated into a markedly higher epidemic potential in outbreak computer simulations. In addition, African ZIKV strains were significantly more lethal than Asian ZIKV strains in immunocompromised adult mice. Finally, prenatal infection of immunocompetent mouse embryos with an African ZIKV strain resulted in embryonic death whereas it caused microcephaly with Asian ZIKV strains. Together, our results demonstrate the high epidemic potential and pathogenicity of recent ZIKV strains from Africa. Importantly, they also imply that the African ZIKV lineage could more easily go unnoticed by public health surveillance systems than the Asian ZIKV lineage due to its propensity to cause fetal loss rather than birth defects.

Prenatal maternal infections and children's socioemotional outcomes

Previous research suggests that prenatal maternal infections may be associated with increased odds of children having a neurodevelopmental disorder. However, little evidence exists on associations with broader child outcomes, especially subclinical symptoms. Participants were the N = 14,021 members of the population-representative UK Millennium Cohort Study. We examined associations between prenatal maternal infections, both maternal-reported and hospital-recorded, and children’s socioemotional development, using the Strengths and Difficulties Questionnaire (SDQ) at age three. Maternal-reported prenatal infections were associated with increased emotional symptoms, after adjusting for several potential confounds and covariates. Hospital-recorded prenatal infections were not associated with children’s socioemotional outcomes, after adjusting for potential confounding and covarying factors. Findings suggest that prenatal maternal infections, particularly those which the mothers remember months later, may be associated with increased emotional problems in early childhood. This emphasises the need for screening for and preventing infections during pregnancy. Further, the occurrence of prenatal infection indicates the potential need for early intervention for children’s emotional difficulties.

Prenatal maternal infections, ASD and ADHD

No clear answer has yet been attained as to the influence of prenatal exposure to infection on autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), either alone or as co-occurring issues. We examined links between hospital-recorded and maternal-reported prenatal infections and ASD, ADHD and co-occurring ASD and ADHD in a large population-representative UK sample. Significant associations between maternal-reported infections and ASD, ADHD and co-occurring ASD and ADHD were found, but no significant associations were found with hospital-recorded infections. Agreement between hospital-recorded and maternal-reported infections was low, which may explain the discrepant findings. Results point to the importance of drawing on multiple sources of information when determining whether or not a prenatal infection is present.

O10.1. MATERNAL PRENATAL C-REACTIVE PROTEIN, NEURODEVELOPMENT AND OTHER RISK FACTORS FOR PSYCHOSIS IN ADOLESCENT OFFSPRING IN THE NORTHERN FINLAND BIRTH COHORT 1986

Background Prenatal infection is associated with brain structural and functional abnormalities, and may increase risk for psychosis through a direct effect on neurodevelopment. Proinflammatory immune response may be a common mechanism through which various infections exert their harmful effect, but studies of prenatal maternal inflammatory markers and offspring neurodevelopment are scarce. We examined the associations of maternal prenatal C-reactive protein (CRP) levels with psychosis risk factors in adolescent offspring including markers of neurodevelopment and cannabis use. Methods This study used a longitudinal birth cohort, the Northern Finland Birth Cohort 1986 (NFBC 1986), followed up to age 16 years (n=6,985/9,432, 76% follow-up). CRP was measured in maternal sera collected in pregnancy. In offspring, school performance was measured at age 7 and 16y; psychotic experiences and cannabis use was measured at age 16. Controlling for offspring sex, maternal education level, maternal body mass index during pregnancy, smoking during pregnancy and alcohol use during pregnancy using regression analysis, we tested associations of CRP with offspring measures. We also tested for mediation, specifically if adolescent cannabis use mediated the associations between maternal CRP and offspring psychotic experiences and school performance. Results Based on data from a minimum of 4,153 participants, after controlling for offspring sex, maternal education level, maternal body mass index during pregnancy, smoking during pregnancy and alcohol use during pregnancy, maternal CRP was associated with adolescent neurodevelopmental markers, including psychotic experiences (odds ratio=1.13, 95% CI=1.00–1.29) and academic performance at age 16 years (beta=0.063, SE=0.013, 95% CI=0.037–0.089). Maternal CRP was also associated with adolescent cannabis use (odds ratio=1.27, 95% CI=1.11–1.46). Cannabis use appeared to mediate a small amount of the associations between maternal CRP and both psychotic experiences and academic performance. Discussion These results support a neurodevelopmental role for maternal prenatal infection and offspring psychosis but also suggest an indirect effect through increasing risk of exposure to cannabis. Maternal infection and immune activation may impact on brain circuitry involved in impulsivity, increasing behaviours such as cannabis use that are separately associated with psychosis. The results of this study give clues regarding the mechanism of the maternal inflammation – psychosis association and add to our understanding of the complex neurodevelopmental processes predating psychosis.

Prenatal infection with Mycoplasma pulmonis in rats exaggerates the angiotensin II pressor response in adult offspring

Exposure to different stressors in utero is linked to adult diseases such as obesity and hypertension. In this study, the impact of prenatal infection (PNI) on adult body weight and cardiovascular function was evaluated using a naturally occurring rodent pathogen, Mycoplasma pulmonis (MP). Pregnant Sprague-Dawley rats were infected with MP on gestational day 14 and gave birth naturally. Adult PNI offspring weighed more than controls, but resting mean arterial pressure (MAP) was unchanged. Subcutaneous injection of angiotensin II (10 μg/kg) elicited a rise in MAP that was greater in both male and female PNI offspring compared with controls ( P < 0.03). The accompanying reflex bradycardia was similar to the controls, suggesting that PNI induced baroreflex dysfunction. Subcutaneous nicotine administration, a potent cardiorespiratory stimulus, also elicited a transient rise in MAP that was generally greater in the PNI group, but the change in MAP from baseline was only significant in the PNI females compared with controls ( P < 0.03). Elevated body weight and cardiovascular reactivity in the PNI offspring was associated with an increase in the ratio of hypothalamic corticotrophin-releasing hormone receptors type 1 to type 2 gene expression in both sexes compared with controls. These findings support previous studies demonstrating that PNI induces alterations in cardiovascular function and body weight. Yet, unlike previous studies utilizing other models of PNI (e.g., endotoxin), MP PNI did not induce resting hypertension. Thus, our study provides a foundation for future studies evaluating the cardiovascular risks of offspring exposed to microbial challenges in utero.