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Bad Timing: Prenatal Exposure to Maternal STDs Raises Risk of Schizophrenia

22 May 2006. Chasing down environmental risk factors for schizophrenia has led researchers back to the womb, to the very beginning of brain development in fetal life. Epidemiological data point to a mother’s exposure to a range of pathogens as a risk factor for several neuropsychiatric illnesses in her grown children. In particular, research has linked maternal exposure to influenza virus, toxoplasmosis, and rubella to an increased incidence of schizophrenia in adults.

Much of this work has been done by Alan Brown and colleagues at Columbia University in New York, and they can now add to that list a wide range of sexually transmitted microbes. In a paper appearing in the May issue of the American Journal of Psychiatry, Brown and colleagues report that children born to mothers who experienced genital/ reproductive infections around the time of conception or in the first few weeks of pregnancy displayed a five times higher risk of schizophrenia as adults. The time window of susceptibility was quite narrow, as no elevated risk was associated with maternal infection at later gestational times.

One possible explanation of the results is that stimulation of the maternal immune system, rather than direct fetal infection with a particular organism, affects brain development, leading to later problems. Just how that might happen is the subject of another paper, this from the lab of Benjamin Yee at the Swiss Federal Institution of Technology Zurich (Switzerland). Writing in the May 3 issue of the Journal of Neuroscience, Yee and colleagues show that elevation of maternal inflammatory cytokines at different stages of pregnancy in mice causes distinct neurodevelopmental abnormalities in the offspring. By tying maternal and fetal cytokine profiles to changes in neurogenesis, neuronal apoptosis, and adult behavior, this line of research provides a mechanistic footing for the epidemiological work. It is also possible that some individual infections may operate by unique effects to disrupt fetal brain development and increase risk for schizophrenia.

In the first study, lead author Vicki Babulas and her Columbia colleagues searched for a connection between infections of the reproductive tract and schizophrenia in a sampling of mothers and their (now adult) children, in a birth cohort in northern California. Of the 7,794 offspring in the study, 71 were diagnosed with schizophrenia spectrum disorders. To determine the frequency of maternal infection, the researchers reviewed the mothers’ medical records for physician documentation of any of eight diagnoses, including endometritis, cervicitis, pelvic inflammatory disease, vaginitis, gonorrhea, syphilis, condylomata, or venereal disease during four pregnancy intervals—periconception and first, second, or third trimester.

Their results show that when the mother was exposed during the periconceptional period (from 30 days before the last menstrual period to 30 days after), the rate ratio for schizophrenia in the offspring was 5.03 (95 percent CI 2.00-12.64, p = .001), compared to unexposed pregnancies and adjusted for maternal race, education, age, and mental illness. The incidence of rates of schizophrenia did not differ between the offspring of exposed versus unexposed mothers at any other time during pregnancy.

Additional, larger studies will be needed to confirm these findings and clarify which of the many infectious agents involved contribute most to the prenatal risk identified in this study. But if the results are replicated, it opens the possibility that treating and preventing STDs before and during pregnancy could have an immediate impact on the children of infected mothers. The authors write, “It is conceivable that a reduction in the incidence of schizophrenia may be brought about by readily available pharmacotherapeutic and other public health measures.”

Effects of in utero cytokines depend on time of exposure
Infection of mothers might affect development of their babies via changes in both maternal and fetal cytokine levels. To look directly at the effect of maternal cytokines on fetal brain development, dual first authors of the second paper, Urs Meyer and Myriel Nyffeler used a mouse model of acute inflammation during pregnancy that results in behavioral deficits in the offspring (Shi et al., 2003; Meyer et al., 2005). In this model, injecting pregnant mice with a synthetic analog of double-stranded RNA (polyI:C) elicits a strong but transient inflammatory response, and allows studies on the effects on offspring through postnatal life.

By dosing at two different gestational stages, the investigators found distinct patterns of psychopathological outcomes, cytokine production, and brain neuropathology as a result of the timing of inflammation. When they treated with polyI:C at gestational day 9 (thought to be in the vicinity of the first-to-second trimester transition in humans: Kaufman, MH [2003] The atlas of mouse development. London: Academic), the offspring showed significantly reduced exploratory behavior in an open field test as young adolescents. Offspring of mothers who were dosed at day 17 (equivalent to human second-to-third trimester transition) also showed a decrease in exploratory behavior in an open field, but it was much smaller and not statistically significant. The later-treated animals did show significant behavioral changes by a different measure, a reversal-of-choice task, where they took longer to learn the new choice. This perseverative behavior is proposed to model the lack of behavioral flexibility seen in schizophrenia and several other disorders, including autism and obsessive-compulsive disorder.

The neuropathological correlates of these behavioral changes were different in the offspring from earlier or later-treated mouse dams. Gross brain morphology was unaltered, but a closer look showed that the mice that were exposed on P9, and thus experienced inflammation at mid-gestation, had reduced reelin-positive cells in the hippocampus. The mice that experienced inflammation later showed reductions in reelin-expressing cells that were not as severe. Both groups had a loss of newly born neurons in the dentate gyrus of the hippocampus, but only the mice treated later in gestation displayed significantly elevated levels of caspase activation and apoptosis of neurons. The mice also showed different patterns of maternal and fetal production of proinflammatory and anti-inflammatory cytokines, depending on the timing of polyI:C injection.

These results suggest that the same inflammatory stimulus, when present at different gestational stages, can interfere with distinct developmental pathways via stimulation of varying cytokine profiles. If these results translate to humans, then timing of infection and the cytokines induced should be a critical determinant of the type of pathology that shows up in adulthood. This jibes with the current epidemiological study, and previous ones using the same group of patients (Brown et al., 2001; Brown et al., 2004), that link the risk for schizophrenia to infections occurring in a window of vulnerability in early to mid-pregnancy.—Pat McCaffrey.

References:
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry. 2006 May;163(5):927-9. Abstract

Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006 May 3;26(18):4752-62. Abstract

Comments on News and Primary Papers
Comment by:  Paul Patterson
Submitted 22 May 2006
Posted 22 May 2006

Over the past six years, Alan Brown and colleagues have published an impressive series of epidemiological findings on schizophrenia in the offspring of a large cohort of carefully studied pregnant women (reviewed by Brown, 2006). Their work has confirmed and greatly extended prior findings linking maternal infection in the second trimester with increased risk for schizophrenia in the offspring. Moreover, Brown et al. found an association between anti-influenza antibodies in maternal serum and increased risk for schizophrenia, as well as a similar association with elevated levels of a cytokine in maternal serum. In a new paper (Babulas et al., 2006), this group reports a fivefold increase in risk for schizophrenia spectrum disorders in the offspring of women who experienced a genital/reproductive infection during the periconception period. The infections considered were endometritis, cervicitis, pelvic inflammatory disease, vaginitis, syphilis, condylomata, “venereal disease,” and gonorrhea. Strengths of the study include physician documentation of the infections and face-to-face assessments of schizophrenia. Although sample size was modest, these results extend a prior finding that elevated maternal anti-herpes simplex type 2 antibodies are associated with increased risk of psychotic disorders, including schizophrenia (Buka et al., 2001).

The mechanism of how maternal infection increases risk for schizophrenia could involve pathogens invading the fetus. Although this is certainly possible in the case of some of the infections studied by Babulas et al., in the case of a respiratory virus such as influenza, this explanation appears unlikely. A more parsimonious mechanism would involve activation of the maternal immune system, and action of soluble mediators such as cytokines at the level of the placenta or the fetus. Support for this hypothesis comes from animal studies. An antiviral immune response can be evoked in the absence of the pathogen by injection of synthetic double-stranded RNA (polyI:C). When this is done in pregnant rats or mice, the adult offspring display a number of behavioral abnormalities reminiscent of those observed in schizophrenia. These include deficits in prepulse inhibition, latent inhibition, and social interaction, as well as enhanced amphetamine-induced locomotion and anxiety under mildly stressful conditions (Shi et al., 2003; Zuckerman et al., 2003; Ozawa et al., 2005). Moreover, some of these deficits are ameliorated by treatment with antipsychotic drugs and exacerbated by psychotomimetics (Shi et al., 2003; Ozawa et al., 2005), and the offspring also exhibit dopaminergic hyperfunction (Zuckerman et al., 2003; Ozawa et al., 2005). Some of these abnormalities are also seen in the offspring of influenza-infected mothers or mothers injected with the bacterial cell wall component, LPS (Borrell et al., 2002; Fatemi et al., 2002; Shi et al., 2003).

The most recent advance in this growing cottage industry is the finding that there are critical periods of maternal immune activation that determine the type of adult behavioral dysfunction and neuropathology found in the offspring (Meyer et al., 2006). Injection of polyI:C during stages of mouse gestation corresponding to first-to-second versus second-to-third trimesters of human pregnancy yields different deficits in exploratory and perseverative behavior, postnatal reelin expression, and hippocampal apoptosis. Moreover, these two different stages of injection evoke diverse cytokine responses in the fetal brain. It would further be interesting to know which of these abnormalities is specific to the period corresponding to the human second trimester, as this is the key time of vulnerability for risk of schizophrenia associated with maternal infection.

Other fascinating questions for this increasingly popular model are, what mediates the effects of maternal immune activation (e.g., cytokines, antibodies, corticosteroids), and do they act directly on the fetus or via the placenta? Can imaging be used with the rodents to explore dopamine receptor occupancy? Which of the observed pathologies are most relevant for each of the behavioral abnormalities?

References:
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry. 2006 May;163(5):927-9. Abstract Borrell J, Vela JM, Arevalo-Martin A, Molina-Holgado E, Guaza C. Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology. 2002 Feb;26(2):204-15. Abstract Brown AS. Prenatal infection as a risk factor for schizophrenia. Schizophr Bull. 2006 Apr;32(2):200-2. Epub 2006 Feb 9. Abstract Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry. 2001 Nov;58(11):1032-7. Abstract Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, Shi L, Sidwell R. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol. 2002 Feb;22(1):25-33. Abstract Meyer U, Feldon J, Schedlowski M, Yee BK. Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neurosci Biobehav Rev. 2005;29(6):913-47. Abstract Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006 May 3;26(18):4752-62. Abstract Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry. 2006 Mar 15;59(6):546-54. Epub 2005 Oct 26. Abstract Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci. 2003 Jan 1;23(1):297-302. Abstract Zuckerman L, Rehavi M, Nachman R, Weiner I. Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology. 2003 Oct;28(10):1778-89. Abstract

View all comments by Paul PattersonComment by:  Jürgen Zielasek
Submitted 3 June 2006
Posted 3 June 2006

Meyer and coworkers provide interesting new data on the role of the immune system in mediating the damage caused by viral infections during pregnancy on the developing nervous system of the fetus. Not just the timing of the infection appears to be critical, but the developing fetal immune system appears to play a role, too.

Polyinosinic-polycytidylic acid (polyI:C), which was employed by Meyer et al., is frequently used to mimic viral infections. It is a synthetic double-stranded RNA and has adjuvant-effects (Salem et al., 2005). PolyI:C binds to target cells via the "Toll-like receptor 3" (TLR3). TLR3 serves as a receptor in trophoblast cells and uterine epithelial cells mediating local immune activation at the maternal-fetal interface after viral infections (Abrahams et al., 2005; Schaefer et al., 2005). Glial cells like microglia and astrocytes also express functional TLR3 (Farina et al., 2005; Park et al., 2006; Town et al., 2006). Thus, TLR3 plays an important role in immune responses, and its natural function appears to be immune activation in addition to cross-priming the immune system to virus-infected cells (Schulz et al., 2005). Given the expression of TLR3 at the maternal-fetal interface and on glial cells, the polyI:C-TLR3-model appears to be useful to study the basic mechanisms of viral infections and their consequences for brain development in animal models.

However, several limitations are evident: PolyI:C is not a virus, and different immunological pathways may be activated by intact viruses after binding to their appropriate receptors. Findings from the immune system of rodents cannot be directly transferred to humans, and it may be difficult to dissect—on a molecular level—the protective aspects of an immune response against a viral infection from its putative detrimental effects on human neurodevelopment. Still, such mechanisms may now be studied in the rodent models used by Meyer and coworkers and other groups, and this will help to pave the way for future studies in humans. This will hopefully lead to a better understanding of the role of the immune system and viral infections in the pathogenesis of schizophrenia.

References:

Abrahams VM, Visintin I, Aldo PB, Guller S, Romero R, Mor G. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol. 2005 Dec 15;175(12):8096-104. Abstract

Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E. Preferential expression and function of Toll-like receptor 3 in human astrocytes. J Neuroimmunol. 2005 Feb;159(1-2):12-9. Epub 2004 Nov 11. Abstract

Park C, Lee S, Cho IH, Lee HK, Kim D, Choi SY, Oh SB, Park K, Kim JS, Lee SJ. TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. Glia. 2006 Feb;53(3):248-56. Abstract

Salem ML, Kadima AN, Cole DJ, Gillanders WE. Defining the antigen-specific T-cell response to vaccination and poly(I:C)/TLR3 signaling: evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity. J Immunother. 2005 May-Jun;28(3):220-8. Abstract

Schaefer TM, Fahey JV, Wright JA, Wira CR. Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C). J Immunol. 2005 Jan 15;174(2):992-1002. Abstract

Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljestrom P, Reis e Sousa C. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature. 2005 Feb 24;433(7028):887-92. Epub 2005 Feb 13. Abstract

Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-stranded RNA via TLR3. J Immunol. 2006 Mar 15;176(6):3804-12. Abstract

View all comments by Jürgen Zielasek

Primary Papers: The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology.

Comment by:  Akira Sawa, SRF Advisor
Submitted 5 June 2006
Posted 5 June 2006

I was greatly interested to read the recent article by Benjamin Yee and colleagues. In this article, the authors hypothesized that cytokine-associated inflammatory responses would be important for maternal infection-induced neuropsychiatric conditions. Thus, the authors administered the viral mimic polyriboinosinic-polyribocytidylic acid (polyI:C) into pregnant mouse dams on gestational day 9 or day 17 and examined the effects in the offspring. It is very impressive that an acute insult, depending on the embryonic day, leads to varied brain changes, as well as behavioral alterations, even in adulthood.

One important lesson from this study is how critical it is to use appropriate molecular markers (in this case, caspase-3, reelin, etc.) in dissecting anatomical and histological changes that may potentially occur in animal models for psychiatric conditions. The data clearly indicate that classic Nissl staining is insufficient to detect important molecular changes that may underlie behavioral alterations in these animals. Many laboratories are now generating and characterizing genetically engineered mice for risk genes for schizophrenia (dysbindin, DISC1, COMT, etc.). In these studies, it will be essential to examine alteration of appropriate molecular markers in such mice. Such changes, even if critical, may occur in specific developmental stage(s) transiently, and be compensated for at later time points. This excellent study by Meyer et al. teaches us that systematic approaches for pathological marker(s) are mandatory for all of us in studying animal models for psychiatric conditions.

Due to lack of gliosis and no clear sign of neuronal cell death in autopsied brains from patients with psychiatric conditions, many investigators may be very skeptical of a role for neuronal cell death in psychiatric conditions such as schizophrenia. I fully agree with this opinion at this moment. However, once more reliable mouse models for psychiatric conditions (probably genetically engineered mice with risk genes) become available, systematic examination for possible involvement of programmed cell death at many developmental time points in mouse models will be beneficial.

In most psychiatric conditions, genetic and environmental interaction is crucial for their pathophysiology, particularly insults during neurodevelopment. Thus, it would be very interesting to test polyI:C or other environmental challenges in mice genetically engineered with risk genes.

View all comments by Akira Sawa

Comments on Related Papers


Related Paper: Prenatal determinants of schizophrenia: what we have learned thus far?

Comment by:  Patricia Estani
Submitted 27 May 2006
Posted 27 May 2006
  I recommend this paper
Comments on Related News


Related News: Urban Schizophrenia Risk: A Family Affair?

Comment by:  Patricia Estani
Submitted 13 June 2006
Posted 13 June 2006
  I recommend the Primary Papers

Related News: Urban Schizophrenia Risk: A Family Affair?

Comment by:  Ella Matthews
Submitted 16 June 2006
Posted 5 July 2006

Questions on the different rates of occurrence of the schizophrenia spectrum of brain disorders between northern (developed) and southern underdeveloped countries, between urban and rural, as well as the birth order within the family of those suffering from schizophrenia are important ones.

However, when thinking about family exposure to environmental factors, I think that there is much to learn from social science. Say that a 1970s family moved from the country to the city just at the time when the birth control pill had been developed and began to be widely available in urban industrialized areas: Estrogen levels on the early formulations of the "pill" were too high, causing women to search for other legal birth control methods which they could tolerate more easily. About the only other things that doctors could offer women back then were the highly touted IUDs.

Say also that a woman tried the birth control pill but, because her taking of the pill was spotty, she became pregnant with her first child. After delivering their first children, many 1970s women then turned to IUDs, which did not cause bloating or the other nasty physical side effects of the pill. What IUDs did have was a hidden wicking string. Those strings were ladders for infection moving into the uterus. So when thinking of environmental factors at the level of the family, one has to ask broad-spectrum socioeconomic questions about what families were actually up against in the 1970s.

Birth control methods could also add insight into why schizophrenia was identified in the late 1800s, a time when women were moving into paid labor outside the home. It had been common knowledge since ancient times that any foreign object inserted into the uterus (IUD) would interfere with pregnancy. Working women had to limit the number of children they had. There was information-sharing among female coworkers.

Think about the implications of IUD use in Catholic countries such as Ireland, which has a high rate of schizophrenia. Catholic mothers of schizophrenics would be loath to discuss birth control methods used prior to or during the birth of a child born with schizophrenia. Moreover, during the Dalkon Shield scandal and IUD birth defect lawsuits of the 1970s and 1980s, the schizophrenias did not get any coverage because children born with these disorders hadn't reached the age of onset yet.

I am a parent of a second-born adult daughter suffering from schizophrenia. Families, especially mothers, do not want to go back to the days when it was said that bad mothering caused schizophrenia. Yet, we who carried these children to term have to ask ourselves what was different going into and throughout these pregnancies?

Skilled researchers need to formulate and ask probing questions about what the mother was exposed to prior to and during these pregnancies.

View all comments by Ella Matthews