Rick--fits into your theory of maternal exposure to infection as causative in PD. madelyn

Science 26 October 2007:
Vol. 318. no. 5850, pp. 576 - 577
DOI: 10.1126/science.1150196



Maternal Effects on Schizophrenia Risk
Paul H. Patterson*
Understandably, there is great enthusiasm surrounding the search for candidate genes that increase the risk for devastating mental disorders such as schizophrenia. Progress is being made on several fronts, such as identifying genes that regulate potential molecular pathways underlying brain development. Genetic variants are also being associated with brain functions during particular cognitive tasks. What is equally important, though, and at risk of being lost in this gene fervor, is a balanced view of the variety of risk factors for mental illness. Many mental disorders are now referred to as "genetic diseases" as if they were autosomal dominant, like Huntington's disease, in which inheriting a genetic mutation causes the disorder in every person. In the case of schizophrenia, recent epidemiological and animal studies are taking understanding of environmental influences to the molecular level.

Much of the emphasis on the genetics of schizophrenia comes from twin studies, where the incidence of the disorder in genetically identical (monozygotic) twins is 50%. This 50% concordance leaves considerable room for nongenetic influences. However, even that figure may be an overestimate of the role of genetic influence (1). Several lines of evidence point to a key role for maternal environment.

Not widely appreciated in deducing the importance of genes from twin studies is the fact that two-thirds of monozygotic twins share a placenta, which is a key environmental factor. Individual placentas vary with respect to the transport of various nutrients and hormones (2), which affects normal development. Interestingly, X-chromosome inactivation is affected by placental status (3) and, in the largest study of its kind, so is IQ (4). It is therefore possible that the placental environment can influence the expression of genes that are linked to neurodevelopment and schizophrenia. Moreover, indirect evidence suggests that monozygotic twins sharing a placenta have a higher concordance for schizophrenia than monozygotic twins with separate placentas (5, 6). It would be extremely informative to directly assess placental status in twin studies of schizophrenia, and there are twin registries where this could be done (7).

Placental status could also influence fetal responses to infectious agents in the mother. For instance, twins sharing a placenta are bathed in the identical blood supply of cytokines that are induced by maternal infection. Moreover, sharing a placenta increases the risk for infection in twins (8). Birth in winter or spring months, when respiratory infections are frequent, is a well-established risk factor for schizophrenia, and most ecological studies of influenza report an increased incidence among offspring born to mothers who were in the second trimester of pregnancy during an epidemic (9). Most importantly, a recent prospective study found that maternal respiratory infection increases the risk for schizophrenia in the offspring three-to sevenfold. Because of the high prevalence of influenza infection, Brown et al. estimate that 14 to 21% of schizophrenia cases would have been prevented if maternal infection had not occurred (9). Moreover, there is an association between elevated concentrations of cytokines or antibodies to influenza antigens in maternal serum and the incidence of schizophrenia in offspring (9). Maternal infection may also play a role in the pathogenesis of autism (10), although more epidemiology is needed here. Such links are remarkable, considering that elevated risk may only be in genetically susceptible individuals. If so, the risk associated with maternal infection in that subgroup would be considerably greater than three-to sevenfold.


The maternal environment. Alterations in fetal brain development, and their associated behavioral changes, have been linked to the placental environment in human and animal studies. Image is a color mezzotint from Gautier D'Agoty, Anatomie des parties de la génération de l'homme et de la femme (1773).
CREDITS: YALE UNIVERSITY, HARVEY CUSHING/JOHN HAY WHITNEY MEDICAL LIBRARY


Although epidemiological studies cannot establish causality, recent work with animals provides experimental evidence that maternal respiratory infection can influence the physiology, behavior, and neuropathology of adult offspring. For instance, maternal influenza infection in rodents causes abnormal behaviors in adult offspring that are consistent with those seen in schizophrenia and autism. These include deficits in social interaction, working memory, prepulse inhibition, and latent inhibition. The latter deficits display postpubertal onset and are normalized by antipsychotic drug treatment. Maternal infection in rodents is also associated with elevated anxiety and neuropathology in offspring that is consistent with that observed in schizophrenia (11, 12).
Changes in the behavior and neuropathology of the rodent offspring are also elicited by injection of synthetic double-stranded RNA into the mother, which evokes an antiviral-like inflammatory response (12-14). Molecular manipulation in this model shows that behavior of the adult offspring results from the balance of pro-versus anti-inflammatory cytokines produced by the mother. That is, blocking pro-inflammatory interleukin-6 or increasing the concentration of anti-inflammatory interleukin-10 strongly attenuates the effects of maternal immune activation on fetal brain development (15, 16). Similar findings have been reported for a model in which maternal bacterial infection is mimicked in rodents by injection of lipopolysaccharide, an immunogenic bacterial component (17).

Although a genetic element clearly contributes to schizophrenia and other mental disorders, the maternal-fetal environment must also be taken into account. Environment can alter genetic outcomes and vice versa, and future research must both tease the two influences apart and consider them together to better understand the onset, progression, and treatment of mental disorders.

References

E. F. Torrey, Schizophr. Bull. 18, 159 (1992).
B. C. Ryan, J. G. Vandenbergh, Neurosci. Biobehav. Rev. 26, 665 (2002).
J. Monteiro et al., Am. J. Hum. Genet. 63, 339 (1998).
N. Jacobs et al., Behav. Genet. 31, 209 (2001).
J. O. Davis, J. A. Phelps, H. S. Bracha, Schizophr. Bull. 21, 357 (1995).
A. Rosa et al., Schizophr. Bull. 28, 697 (2006).
C. A. Derom et al., Twin Res. Hum. Gen. 9, 733 (2006).
D. T. Phung et al., Am. J. Obstet. Gynecol. 186, 1041 (2002).
A. S. Brown, Schizophr. Bull. 32, 200 (2006).
S. L. Hyman, T. L. Arndt, P. M. Rodier, Int. Rev. Res. Ment. Retard. 30, 171 (2006).
S. H. Fatemi et al., Cell. Mol. Neurobiol. 22, 25 (2002).
L. Shi, S. H. Fatemi, R. W. Sidwell, P. H. Patterson, J. Neurosci. 23, 297 (2003).
L. Zuckerman, M. Rehavi, R. Nachman, I. Weiner, Neuropsychopharmacology 28, 1778 (2003).
U. Meyer, B. K. Yee, J. Feldon, Neuroscientist 13, 241 (2007).
S. E. P. Smith, J. Li, K. Garbett, K. Mirnics, P. H. Patterson, J. Neurosci. 27, 10695 (2007).
U. Meyer et al., Mol. Psychiatry, 10.1038/sj.mp.4002042 (2007).
S. A. Robertson, R. J. Skinner, A. S. Care, J. Immunol. 177, 4888 (2006).

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The author is in the Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. E-mail: php@caltech.edu

Not only schizophrenia, but a whole spectrum of disorders such as autism, asperger's, CFS, fibromyalgia, IBS, etc. can be traced back to endotoxin exposure in utero.

One of the characteristics of schizophrenics sometimes is the inability to seperate out or to focus upon relevant data from the general noise from their environment. When I'm off, that pretty much describes things. Autistics are so overwhelmed by the sensory flood that they withdraw to escape. Sounds like me first thing in the morning.

That kind of thing can arise just from the endotoxins. Add in the stress hormones and you've got a real situation on your hands.