Induction of Toll-Like Receptor 3-Mediated Immunity during Gestation Inhibits Cortical Neurogenesis and Causes Behavioral Disturbances

Maternal infection during pregnancy with a wide range of RNA and DNA viruses is associated with increased risk for schizophrenia and autism in their offspring. A common feature in these exposures is that virus replication induces innate immunity through interaction with Toll-like receptors (TLRs). We employed a mouse model wherein pregnant mice were exposed to polyinosinic-polycytidylic acid [poly(I  ⋅  C)], a synthetic, double-stranded RNA molecular mimic of replicating virus. Poly(I ⋅ C) inhibited embryonic neuronal stem cell replication and population of the superficial layers of the neocortex by neurons. Poly(I ⋅ C) also led to impaired neonatal locomotor development and abnormal sensorimotor gating responses in adult offspring. Using Toll-like receptor 3 (TLR3)-deficient mice, we established that these effects were dependent on TLR3. Inhibition of stem cell proliferation was also abrogated by pretreatment with the nonsteroidal anti-inflammatory drug (NSAID) carprofen, a cyclooxygenase (COX) inhibitor. Our findings provide insights into mechanisms by which maternal infection can induce subtle neuropathology and behavioral dysfunction, and they may suggest strategies for reducing the risk of neuropsychiatric disorders subsequent to prenatal exposures to pathogens and other triggers of innate immunity

Can we understand modern humans without considering pathogens?

Throughout our evolutionary history, humankind has always lived in contact with large numbers of pathogens. Some cultural traits, such as sedentarization and animal domestication, have considerably increased new parasitic contacts and epidemic transitions. Here, we review the various phenotypic traits that have been proposed to be affected by the highly parasitic human environment, including fertility, birth weight, fluctuating asymmetry, body odours, food recipes, sexual behaviour, pregnancy sickness, language, religion and intellectual quotient. We also discuss how such knowledge is important to understanding several aspects of the current problems faced by humanity in our changing world and to predicting the long-term consequences of parasite eradication policies on our health and well-being. The study of the evolutionary interactions between humans and parasites is a burgeoning and most promising field, as demonstrated by the recent increasing popularity of Darwinian medicine

Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model

Objectives: Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood. Method: We used an established mouse model of maternal immune activation (MIA) by the viral mimic Polyl:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities. Results: Polyl:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4th ventricle volume but did not disrupt sensorimotor gating. Conclusions: Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life. © 2009 Li et al.published_or_final_versio

Association Between Prenatal Exposure to Bacterial Infection and Risk of Schizophrenia

Recent research suggests that prenatal exposure to nonviral infection may be associated with increased risk of schizophrenia, and we hypothesized an association between maternal bacterial infection during pregnancy and elevated offspring risk of schizophrenia. Data on maternal infections from the Copenhagen Perinatal Cohort were linked with the Danish National Psychiatric Register. Offspring cases of narrowly defined schizophrenia (International Classification of Diseases, Eighth Revision [ICD-8]) and more broadly defined schizophrenia (ICD-8 and ICD-10) were identified before the ages of 32–34 and 45–47 years, respectively. The effect of prenatal exposure to bacterial infections was adjusted for prenatal exposure to analgesics and parental social status. In a risk set of 7941 individuals, 85 cases (1.1%) of ICD-8 schizophrenia were identified by the age of 32–34 years and 153 cases (1.9%) of more broadly defined schizophrenia by the age of 45–47 years. First-trimester exposure conferred an elevated risk of ICD-8 schizophrenia (odds ratio 2.53; 95% confidence interval [CI] 1.07–5.96) and also of broadly defined schizophrenia (odds ratio 2.14; 95% CI 1.06–4.31). Second-trimester exposure also conferred a significantly elevated risk of schizophrenia but only in unadjusted analyses. These findings suggest a relationship between maternal bacterial infection in pregnancy and offspring risk of schizophrenia, and this effect was somewhat stronger for ICD-8 schizophrenia with earlier onset. Post hoc analyses showed that upper respiratory tract and gonococcal infections were associated with elevated risk of the disease. An association between risk of schizophrenia and prenatal exposure to bacterial infections might be mediated through transplacental passage of maternally produced cytokines in response to bacterial infections

Associations between self-reported symptoms of prenatal maternal infection and post-traumatic stress disorder in offspring: Evidence from a prospective birth cohort study

© 2015 Elsevier B.V. All rights reserved. Objective Consistent evidence has linked a range of prenatal maternal infections with psychotic disorders in later life. However, the potential for this exposure to impact more common disorders requires further investigation. Methods Participants came from the Mater University Study of pregnancy, a longitudinal, pre-birth cohort study which recruited pregnant mothers from a Brisbane hospital between 1981 and 1984. At age 21, 2439 offspring completed the CIDI-Auto. Multivariate logistic regression was used to investigate associations of self-reported symptoms of prenatal infection with a range of DSM-IV anxiety and affective diagnoses, while also testing for gender interactions. Results In multivariate analyses, self-reported symptoms of prenatal genital infection predicted Post-traumatic stress disorders (OR=2.38, 95% CI: 1.14, 4.95) and social phobias (OR=1.93, 95% CI: 1.03, 3.61), in addition to evidence for a gender interaction by which males (OR=6.04, 95% CI: 2.00, 18.30) but not females were at greater risk for PTSD. Further analyses among those with PTSD revealed the relationship to be stronger when excluding those not exposed to trauma (OR=3.21, 95% CI: 1.53, 6.72). Limitations We were unable to clinically or serologically verify the presence and the type of prenatal genital infection. Conclusion This is the first study to show an association between self-reported symptoms of prenatal genital infections and two highly prevalent anxiety disorders among adult offspring. The relationship with PTSD was particularly strong and suggested that the exposure may primarily impact PTSD in males. Further research with the capacity to assess a fuller-range of specific prenatal infections is warranted to evaluate the potential of reducing the prevalence of these disorders