Maternal Exposure to Herpes Simplex Virus and Risk of Psychosis Among Adult Offspring

Brown University Department of Community Health, Providence, Rhode Island 02806, USA.
Biological psychiatry (Impact Factor: 10.26). 05/2008; 63(8):809-15. DOI: 10.1016/j.biopsych.2007.09.022
Source: PubMed

ABSTRACT Viral exposure during gestation is thought to be a risk factor for schizophrenia. Previous studies have indicated that prenatal exposure to herpes simplex virus type 2 (HSV-2) may be a risk for the subsequent development of schizophrenia in some populations. In this investigation, we tested a large and diverse population to assess the risk of psychoses among offspring of mothers with serological evidence of HSV-2 infection.
We conducted a nested case-control study of 200 adults with psychoses and 554 matched control subjects (matched for city and date of birth, race/ethnicity, gender, and parent history of treatment for mental disorder) from three cohorts of the Collaborative Perinatal Project (Boston, Providence, and Philadelphia). We analyzed stored serum samples that had been obtained from these mothers at the end of pregnancy for antibodies directed at HSV-2, using type-specific solid-phase enzyme immunoassay techniques.
Offspring of mothers with serologic evidence of HSV-2 infection were at significantly increased risk for the development of psychoses (odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.1-2.3). This risk was particularly elevated among women with high rates of sexual activity during pregnancy (OR = 2.6; 95% CI = 1.4-4.6).
Maternal exposure to herpes simplex virus type 2 is associated with an increased risk for psychoses among adult offspring. These results are consistent with a general model of risk resulting from enhanced maternal immune activation during pregnancy.

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    • "Influenza has been the most widely studied pathogen in the MIA literature, because of its prevalence in the general population. Other studies have, however, revealed that less prevalent infections and viruses including bacterial infections (Clarke et al., 2009; Sorensen et al., 2009), bronchopneumonia (Brown et al., 2000), polio (Suvisaari et al., 1999; Cahill et al., 2002), herpes simplex virus (Buka et al., 2001, 2008; Babulas et al., 2006), rubella (Brown et al., 2000, 2001), and toxoplasma gondii (Brown et al., 2005; Mortensen et al., 2007) are also associated with increased risk for schizophrenia in the offspring of those infected. This common effect across various infections suggests that a specific infection or virus does not, in and of itself, increase the risk of schizophrenia. "
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    ABSTRACT: Maternal exposure to infection occurring mid-gestation produces a three-fold increase in the risk of schizophrenia in the offspring. The critical initiating factor appears to be the maternal immune activation (MIA) that follows infection. This process can be induced in rodents by exposure of pregnant dams to the viral mimic Poly I:C, which triggers an immune response that results in structural, functional, behavioral, and electrophysiological phenotypes in the adult offspring that model those seen in schizophrenia. We used this model to explore the role of synchronization in brain neural networks, a process thought to be dysfunctional in schizophrenia and previously associated with positive, negative, and cognitive symptoms of schizophrenia. Exposure of pregnant dams to Poly I:C on GD15 produced an impairment in long-range neural synchrony in adult offspring between two regions implicated in schizophrenia pathology; the hippocampus and the medial prefrontal cortex (mPFC). This reduction in synchrony was ameliorated by acute doses of the antipsychotic clozapine. MIA animals have previously been shown to have impaired pre-pulse inhibition (PPI), a gold-standard measure of schizophrenia-like deficits in animal models. Our data showed that deficits in synchrony were positively correlated with the impairments in PPI. Subsequent analysis of LFP activity during the PPI response also showed that reduced coupling between the mPFC and the hippocampus following processing of the pre-pulse was associated with reduced PPI. The ability of the MIA intervention to model neurodevelopmental aspects of schizophrenia pathology provides a useful platform from which to investigate the ontogeny of aberrant synchronous processes. Further, the way in which the model expresses translatable deficits such as aberrant synchrony and reduced PPI will allow researchers to explore novel intervention strategies targeted to these changes.
    Frontiers in Behavioral Neuroscience 12/2013; 7:217. DOI:10.3389/fnbeh.2013.00217 · 3.27 Impact Factor
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    • "Time of exposure Infectious agent Effect size a Study Cohort Around conception Genital/reproductive infection 5 Babulas et al. 2006 PDS First trimester Influenza 7 Brown et al. 2004a PDS Bacterial infection 2 Sorensen et al. 2009 Copenhagen perinatal cohort Second trimester Influenza b 3 Brown et al. 2004a PDS Respiratory infection 2 Brown et al. 2000 Third trimester or at delivery HSV-2 1.5 Buka et al. 2001, 2008 and Xiao et al. 2009 NCPP Toxoplasma gondii 2 Brown et al. 2005 PDS Mortensen et al. 2007, 2010 Danish cohorts "
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    ABSTRACT: BACKGROUND: Disruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies.Method Electronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review. RESULTS: Results for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) and Toxoplasma gondii was mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia. CONCLUSIONS: Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a 'sensitive period' during development, and the effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection.
    Psychological Medicine 04/2012; 43(2):1-19. DOI:10.1017/S0033291712000736 · 5.94 Impact Factor
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    • "In a pioneer study Mednick and colleagues have observed that children in utero during the 1957 influenza epidemic had increased risk of developing schizophrenia [2]. The association between influenza exposure during pregnancy and schizophrenia symptoms has been confirmed by several studies (reviewed in [3]) and extended to many other pathogens including other viruses (HSV-2 [4], rubella [5], bacteria [6]), and even protozoan [7], [8] reviewed in[9]). These observations have led to the development of animal models of prenatal infection to better understand how infection during pregnancy contributes to the disease, and whether prenatal infection can be a useful model to understand schizophrenia. "
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    ABSTRACT: Post-mortem studies suggest that GABAergic neurotransmission is impaired in schizophrenia. However, it remains unclear if these changes occur early during development and how they impact overall network activity. To investigate this, we used a mouse model of prenatal infection with the viral mimic, polyriboinosinic-polyribocytidilic acid (poly I:C), a model based on epidemiological evidence that an immune challenge during pregnancy increases the prevalence of schizophrenia in the offspring. We found that prenatal infection reduced the density of parvalbumin- but not somatostatin-positive interneurons in the CA1 area of the hippocampus and strongly reduced the strength of inhibition early during postnatal development. Furthermore, using an intact hippocampal preparation in vitro, we found reduced theta oscillation generated in the CA1 area. Taken together, these results suggest that redistribution in excitatory and inhibitory transmission locally in the CA1 is associated with a significant alteration in network function. Furthermore, given the role of theta rhythm in memory, our results demonstrate how a risk factor for schizophrenia can affect network function early in development that could contribute to cognitive deficits observed later in the disease.
    PLoS ONE 01/2012; 7(1):e29754. DOI:10.1371/journal.pone.0029754 · 3.23 Impact Factor
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