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: 12.3). 03/2010; 167(3):261-80. DOI: 10.1176/appi.ajp.2009.09030361
Source: PubMed


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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    • "Maternal infectious or inflammatory insults during pregnancy have been repeatedly implicated in the etiology of developmental neuropsychiatric disorders, including schizophrenia (Brown and Derkits, 2010; Canetta et al., 2014b), autism (Atladóttir et al., 2012; Brown et al., 2014), and bipolar disorder (Canetta et al., 2014a; Parboosing et al., 2013). Preclinical support for these epidemiological associations has been obtained by various translational rodent models demonstrating multiple brain and behavioral abnormalities following prenatal exposure to infection and/or immune activation (reviewed in Boksa (2010), Harvey and Boksa (2012), Meyer (2014), Meyer and Feldon (2010)). "
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    ABSTRACT: Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre- and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1β levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation.
    Brain Behavior and Immunity 09/2015; DOI:10.1016/j.bbi.2015.09.015 · 5.89 Impact Factor
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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, 2mg/kg/day) or olanzapine (OLZ, 10mg/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 contribution of antipsychotic medication to markers of brain inflammation. Further investigation of the links between antipsychotic treatment and the immune system are warranted. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European Neuropsychopharmacology 08/2015; DOI:10.1016/j.euroneuro.2015.08.004 · 4.37 Impact Factor
    • "An evidence for this hypothesis is the 5–8% increased risk of developing schizophrenia among those born in the winter–spring months, when infectious diseases are more prevalent (O'Callaghan et al., 1991). Moreover, serological studies have shown an elevation in risk of schizophrenia following exposure to several agents during gestation (Brown et al., 2004a, 2005; Buka et al., 2008; Brown and Derkits, 2010). Besides, some studies reported an association between higher level of Contents lists available at ScienceDirect journal homepage: "
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    ABSTRACT: Although several studies suggest a virus or (endogenous) retrovirus involvement at the time of onset of schizophrenia, the unequivocal identification of one or more infectious agents, by means of an undirected catch-all technique, has never been conducted. In this study VIDISCA, a virus discovery method, was used in combination with Roche-454 high-throughput sequencing as a tool to determine the possible presence of viruses (known or unknown) in blood of first-onset drugs-naïve schizophrenic patients with prominent negative symptoms. Two viruses (the Anellovirus Torque Teno virus and GB virus C) were detected. Both viruses are commonly found in healthy individuals and no clear link with disease was ever established. Viruses from the family Anelloviridae were also identified in the control population (4.8%). Besides, one patient sample was positive for human endogenous retroviruses type K (HML-2) RNA but no specific predominant strain was detected, instead 119 different variants were found. In conclusion, these findings indicate no evidence for viral or endogenous retroviral involvement in sera at the time of onset of schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    08/2015; 229(3). DOI:10.1016/j.psychres.2015.08.025
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