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.