The Viral Theory of Schizophrenia

Contributed by guest blogger: Hannah Ziobrowski ’12

Schizophrenia is a severely debilitating mental illness with no known cause or cure, although there is a strong genetic correlation.  Interestingly, there is additionally a significant relationship between season of birth and the development of schizophrenia, as individuals born during late winter and spring have a significantly increased risk for developing schizophrenia.  One hypothesis to explain this phenomenon is that this is due to prenatal viral infection, which is more likely to occur in the winter months.  It is hypothesized that viral infections occurring during the third trimester of pregnancy result in the increased risk for developing schizophrenia.  However, there is currently debate as to how this happens- is it due to a direct viral infection of the fetus, or due to maternal cytokines in response to infection?

A study by Faterni et al (2012) found that the placenta may be a site of pathology in viral infections.  Using pregnant mice infected with a sublethal dose of influenza on the seventh day of pregnancy (E7), they found that viral infection resulted in many histological abnormalities in the placentae.  These abnormalities included an absence of the labyrinth zone, the region of the maternal placenta in which nutrients and oxygen are exchanged between the maternal and fetal blood, the presence of thrombi, and an increased number of inflammatory cells.  Additionally, microarray analyses revealed a significant upregulation of 77 genes and downregulaton of 93 genes in the placentae of infected mothers, compared to sham-infected mothers.  20% of these altered genes were involved in apoptotic or anti-apoptotic pathways, 10% were associated with immune response, 11% were involved with hypoxia, and about 11% were involved with inflammation.  9.4% were associated with major mental disorders including schizophrenia, bipolar disorder, major depression, and autism.  All of these changes could potentially affect developing embryos.  The deletion of a labyrinth zone could result in a reduction of oxygen delivered to the developing fetus and result in neural abnormalities, which may be ultimately caused by an inflammatory immune response.

The authors also analyzed gene expression in the hippocampus and prefrontal cortex of the offspring of infected mothers.  Compared to offspring of sham-infected mothers, they found 6 upregulated and 24 downregulated genes in the prefrontal cortex at the first day after birth (P0), and 4 upregulated and 13 downregulated genes in the hippocampus at P0.  Genes in the prefrontal cortex that showed a significant alteration in expression included glutamate receptor interacting protein I, platelet factor 4, contactin 1, and neurotrophic tyrosine kinase receptor type 3.  Important genes in the hippocampus that showed altered levels of expression included paralemmin 2, and protein tyrosine kinase 2 beta.  In total, 40 different genes showed altered expression in the two areas at P0 after infection at E7 (first trimester), compared to 39 at E9, 676 at E16, and 247 at E18 (as found in previous studies).   These altered expression levels most likely reflect altered neural organization.

Importantly, HINI viral genes were not detected in either the placenta or brains of offspring whose mothers were infected at E7, suggesting that the virus did not cross the placenta to directly infect the offspring.  This consequently implicates that the changes found in gene expression as well as the structural abnormalities of the placenta were most likely due to the production of maternal or fetal cytokines, most likely due to an increase in inflammatory cells in infected placenta.

These data overall illustrate that viral infections during pregnancy can lead to an inflammatory response and structural abnormalities in the placenta.  These structural abnormalities may cause significant alterations in oxygen and nutrients delivered to the fetus, causing abnormalities in the overall development of the fetus, including the brain.  Could these organizational neural abnormalities lead to an increased risk for developing schizophrenia later in life?

A next step for the authors would be to directly check the levels of cytokines in the placenta in order to assess the inflammatory response. Furthermore, are these results also found with infection of other viruses?  Or are they more or less significant depending on the virus and time of infection?


Hannah Ziobrowski is a senior at Vassar College, majoring in Neuroscience and Behavior.



21 thoughts on “The Viral Theory of Schizophrenia”

  1. Not as far as I know. While ere may be a genetic component to schizophrenia, I dont think that specific genes that have been identified that have a strong causative relationship with the disease.

  2. Hello,
    I was wondering if there are any tests that can be performed on parents to identify if they are carrying a higher risk of having anything in their genes that could transmit schizophrenia or another disorder to their babies?

    Regards, Andreas

  3. I was also wondering the same thing as Alejandro stated earlier. In my psychology class this semester we discussed the predisposing factors and conditions that contribute to developing mental disorders such as schizophrenia, but no biological factors were discussed, with the exception of genetics. This was also the case for other mental disorders. I’m wondering if finding ways to treat this viral infection (or prevent it from affecting fetal development) would result in a significant change in the frequency of schizophrenia cases.

  4. That’s quite interesting; I hadn’t realized that certain viral infections (such as HIV) affected the fetus during birth and not during prenatal development. I had never considered the ability of the placenta to selectively prevent the passage of certain substances. This of course makes a lot of sense due to viruses’ ability to infect different types of cells depending on their specific structure.

  5. I found this blog post to be an interesting read and very informative. I would never think that the diagnosis of schizophrenia could be related to viral infections during pregnancy. Often, when individuals talk about schizophrenia, they often assume that its development is due to genetics and/or severe social or psychological trauma, but never due to viral infections. I would definately share this information with others.

  6. I found the article very interesting. It makes me wonder what other psychological disorders can be linked to viral theories.

  7. I found this article very interesting and relevant to the discussion on how viruses affect individuals, even those that have not been born yet. I had previously heard that of the hypothesis regarding the idea that schizophrenia might be caused by viral infection during pregnancy and thus it was very interesting to read commentary on a research paper that had actually experimented and studied the subject area. What I found most interesting from the article was the way in which many of the observations that were seen in the alterations of the brain correlated with the theories behind what scientists speculate cause schizophrenia. For example a region that the scientist saw was affected was the prefrontal cortex, in patients with schizophrenia this area is associated with the production of negative symptoms due to what scientist speculate to be hypofrontality, or decreased activity of the frontal lobes. The alterations that they saw in the glutamergic receptors might also support the theories behind the dopamine hypothesis, in which scientist assume that if glutamate receptors are inhibited, neuronal communication will also prompt a decrease in the level of dopamine being produced in the prefrontal cortex, causing hypofrontality. This hypofrontality will affect other regions of the brain and their dopamine levels causing the onset of positive and cognitive symptoms. Alas although these observations make sense and might seem to insinuate that viral infection during pregnancy might be a cause of schizophrenia nothing is certain and more research should be conducted. That way if there is a correlation, scientist will be able to know if it is a result of the body’s immune response or the virus directly affecting brain development, and create ways that might reduce the likelihood of the child developing a disorder like schizophrenia

  8. Correlation between schizophrenia and season of birth is something that I would normally think of as far-fetched. I was wondering what researchers do to test mental disabilities in mice, do they look at genes or levels of chemicals in the brain characteristic of schizophrenia? I would also like to know if, as the article asked, the researchers had considered these defects in the placenta in relation to other viruses and other disorders.

  9. It is interesting that there is a correlation between season of birth and the development of schizophrenia. However, I don’t know how relevant that information is because it could simply be an coincidence. That being said, wouldn’t viral infections increase the risks of developing other mental disorders besides schizophrenia? In addition, according to the New York Times, schizophrenia develops between the ages of 15 & 24 for men and 25 & 34 for women. Therefore how would this new study account/explain why there is such a huge delay between the mother being infected by a virus while the child is a fetus and the offspring actually developing schizophrenia later on in life? Also why would there be such a drastic difference between when males and females develop schizophrenia if the mothers were all infected with the same virus?

  10. Thats a good point – should mothers do anything out of the ordinary to prevent infection to avoid this risk. I think it is always important not to consider early research as medical advice. Its a correlation, and is far from being shown to be anything more. The risks to the fetus from the medications are likely higher than the hypthetical risk of developmental disorders following infection. The best would likely be vaccination, and as you say, hygene, to avoid getting the virus in the first place.
    Schizophrenia is not the only condition correlated with season of birth – multiple sclerosis is too. There has long been a search for an infectious basis for MS too, but also remains poorly supported (at best).

  11. Im certainly no expert on this, but my understanding is that the placenta is a pretty good selective barrier. Something like alcohol can get through to the fetus, causing developmental problems like fetal alcohol syndrome, while others are blocked from getting through. For viruses, the rubella virus can be transmitted from infected mother to the fetus, presumably through the placenta, but I dont know for sure. HIV on the other hand doesnt seem to infect the fetus of HIV positive mothers (although infection during birth can occur). It likely has to do with what type of cells the virus can infect, to allow it to gain access to the fetus.

  12. I found it very interesting that the virus in this study did not transfer and infect the fetus directly. I have heard of mothers passing on certain disorders, such as drug dependency, onto their fetuses/babies. I was wondering why certain diseases, disorders would infect the fetus while others would not.

  13. I also thought that this was a very interesting experiment; I would not have thought to link the season of birth to the later development of schizophrenia. I wonder though, if there is a legitimate correlation between the two, how could neurological damage be prevented in the future for the fetus? If I am correct, I believe that pregnant women are instructed to refrain from ingesting particular flu/cold medications, as they themselves could also harm the fetus. So aside from the practice of excellent hygiene, which does not necessarily guarantee that one will not contract a virus, how can we prevent the mother’s immune system from performing its proper function, even if it does cause harm to the fetus?

  14. This is a very interesting study that makes me want to learn more about how physiological and neurological responses to infection can cause psychopathology. I know that in general, people with depression exhibit more inflammatory biomarkers and I’m wondering if this too could be caused by an immune response, perhaps in utero.

  15. More precisely worded, perhaps: it seems that this viral basis for schizophrenia would be applicable only for people with moderate or severe physical and mental disabilities because of the damage to the labyrinth zone. I would like to see a follow-up study done for schizophrenia in otherwise neurologically “normal” patients, or at least to see information about the other compromising effects of viral infection on the fetus.

  16. I think you and I had a similar question. What exactly about viral expression makes it such that the transfer of nutrients between the fetus and mother is damaged? And — my follow-up question — shouldn’t that be detrimental to the fetus (i.e. severely stunt growth or cause death in the womb)?

  17. Upregulated means that gene expression is turned on or up, while downregulated means that the expression of a gene is turned off or down. Genes are only expressed when needed, and cells respond to their environment (such as responding to infection) by turning gene expression on or off, depending on what the cell needs to do.

  18. Just to clarify, there is a correlation with season of birth and schizophrenia, but why that correlation exists, or if it is relevant, is not known. The peak season coincides with flu season but a cause and effect relationship is far from supported. Its an interesting correlation but obviously much more work needs to be done to figure out if there is anything to that correlation.

  19. Super interesting connection between Schizophrenia and season of birth, due to increase susceptibility to viruses. However, I was just wondering what about the virus causes gene alterations making the child more susceptible to Schizophrenia? What are the specific effects of the inflammatory response that cause structural abnormalities in the placenta that decreases the amount of nutrients delivered to the fetus?

  20. Certainly interesting. I wonder in particular about the relationship between infection and the absence of the labyrinth zone. Do you (or does Professor Esteban) know any more about it?

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