Article

Prenatal Infection and Schizophrenia: A Review of Epidemiologic and Translational Studies

Columbia University, New York, New York, United States
American Journal of Psychiatry (Impact Factor: 13.56). 03/2010; 167(3):261-80. DOI: 10.1176/appi.ajp.2009.09030361
Source: PubMed

ABSTRACT An emerging literature from epidemiologic, clinical, and preclinical investigations has provided evidence that gestational exposure to infection contributes to the etiology of schizophrenia. In recent years, these studies have moved from ecologic designs, which ascertain infection based on epidemics in populations, to investigations that have capitalized on reliable biomarkers in individual pregnancies. These studies have documented specific candidate infections that appear to be associated with an elevated risk of schizophrenia. Animal models of maternal immune activation inspired by this work have revealed intriguing findings indicating behavioral, neurochemical, and neurophysiologic abnormalities consistent with observations in schizophrenia. In parallel studies in humans and animals, investigators are working to uncover the cellular and molecular mechanisms by which in utero exposure to infection contributes to schizophrenia risk. In this review, the authors discuss and critically evaluate the epidemiologic literature on in utero exposure to infection and schizophrenia, summarize emerging animal models of maternal immune activation, and discuss putative unique and common mechanisms by which in utero exposure to infection alters neurodevelopment, potentially increasing susceptibility to schizophrenia. The promise of this work for facilitating the identification of susceptibility loci in genetic studies of schizophrenia is illustrated by examples of interaction between in utero exposure to infection and genetic variants. The authors then elaborate on possible implications of this work, including the use of preventive measures for reducing the incidence of schizophrenia. Finally, they discuss new approaches aimed at addressing current challenges in this area of research.

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    • "Multiple lines of evidence suggest a role for the immune response and neuroinflammation in the pathogenesis schizophrenia (SCZ) (Brown and Derkits, 2010; Kahn and Sommer, 2014; Martins-de-Souza et al., 2009; Maxeiner et al., 2014; Miller et al., 2013a; Sommer et al., 2014). Microglia act as the resident macrophages of the brain and are the first cells to respond, mobilizing the inflammatory response to brain insult or injury (Venneti et al., 2006). "
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    ABSTRACT: Neuroinflammation is increasingly implicated in the pathogenesis of Schizophrenia (SCZ). In addition, there is increasing evidence for a relationship between the dose and duration of antipsychotic drug (APD) treatment and reductions in grey matter volume. The potential contribution of microglia to these phenomena is however not yet defined. Adult rats were treated with a common vehicle, haloperidol (HAL, 2 mg/kg/day) or olanzapine (OLZ, 10 mg/kg/ day) for 8 weeks via an osmotic mini-pump implanted subcutaneously. Microglial cells, identified by their Iba-1 immunoreactivity, were quantified in four regions of interest chosen based on previous neuroimaging data: the hippocampus, anterior cingulate cortex, corpus striatum, and secondary somatosensory cortex. Those cells were also analysed according to their morphology, providing an index of their activation state. Chronic APD treatment resulted in increased density of total microglia in the hippocampus, striatum, and somatosensory cortex, but not in the ACC. Importantly, in all brain regions studied, both APD tested led to a dramatic shift towards an amoeboid, reactive, microglial morphology after chronic treatment compared to vehicle-treated controls. These data provide the first in vivo evidence that chronic APD treatment at clinically relevant doses leads to microglial proliferation and morphological changes indicative of activated microglia in the naïve rat brain. Although caution needs to be exerted when extrapolating results from animals to patients, these data suggest a potential
    European Neuropsychopharmacology 08/2015; DOI:10.1016/j.euroneuro.2015.08.004 · 5.40 Impact Factor
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    • "To date, several epidemiological studies have indicated that both maternal bacterial and viral infections during pregnancy increase an offspring's risk of schizophrenia [2], but precisely why these infections seem to act as a risk factor are unclear. However, a growing body of evidence suggests that schizophrenia and certain autoimmune diseases may share some key clinical, epidemiological and genetic features [1]. "
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    ABSTRACT: Epidemiological studies have indicated that both maternal bacterial and viral infections during pregnancy increase the risk of schizophrenia among offspring, but to date there is not clear explanation for this increased risk. Previously, the decreased C4b-binding protein (C4BP), a potent circulating soluble inhibitor of the classical and lectin pathways of complement, was reported to be associated with risk of schizophrenia. Here, we analyzed 4 common single nucleotide polymorphisms (SNPs) of C4BPB and 5 SNPs of C4BPA in a group of 556 schizophrenia patients and a matched group of 610 healthy controls to see if the genes C4BPB and C4BPA, which encode C4BP, may confer a susceptibility to schizophrenia. Comparing the genotype and allele frequencies of those SNPs between cases and controls, we found no association between the C4BPB/C4BPA variants and schizophrenia. Our results provided preliminary evidence that C4BPB/C4BPA may not confer susceptibility to schizophrenia among Han Chinese. Further genetic studies from large-scale population are required to obtain more conclusive results. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Neuroscience Letters 02/2015; 590. DOI:10.1016/j.neulet.2015.02.005 · 2.06 Impact Factor
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    • "This parallels the reduced connectivity seen between these neural systems during working memory tasks in schizophrenia patients. In addition, reduced hippocampal‐prefrontal synchrony has been shown as a result of maternal immune activation (MIA, Dickerson et al., 2010), a translational rodent model based on epidemiological evidence of an increased risk of developing schizophrenia in adulthood following prenatal exposure to infection (Brown et al., 2010). Furthermore, reduced hippocampal‐prefrontal synchrony has also been shown in the widely utilised methylazoxymethanol acetate (MAM) neurodevelopmental model (Dickerson et al., 2010, Phillips et al., 2012, Belujon et al., 2013). "
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    ABSTRACT: While our knowledge of the pathophysiology of schizophrenia has increased dramatically, this has not translated into the development of new and improved drugs to treat this disorder. Human brain imaging and electrophysiological studies have provided dramatic new insight into the mechanisms of brain dysfunction in the disease, with a swathe of recent studies highlighting the differences in functional brain network and neural system connectivity present in the disorder. Only recently has the value of applying these approaches in preclinical rodent models relevant to the disorder started to be recognised. Here we highlight recent findings of altered functional brain connectivity in preclinical rodent models and consider their relevance to those alterations seen in the brains of schizophrenia patients. Furthermore, we highlight the potential translational value of using the paradigm of functional brain connectivity phenotypes in the context of preclinical schizophrenia drug discovery, as a means both to understand the mechanisms of brain dysfunction in the disorder and to reduce the current high attrition rate in schizophrenia drug discovery.
    Journal of Psychopharmacology 01/2015; 29(2). DOI:10.1177/0269881114563635 · 2.81 Impact Factor
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