Schizophrenia, which affects 1% of the world's population, has been linked epidemiologically to prenatal exposure to human influenza virus. Experimental animal data supporting this linkage are lacking. Our long-range goal is to understand how prenatal human influenza viral infection affects brain development adversely, leading to the genesis of schizophrenia. The objective of this application is to determine how prenatal infection of mice with human influenza virus causes subsequent brain structural and behavioral abnormalities in adult animals. The central hypothesis of the application is that prenatal viral infection at critical periods during embryogenesis causes permanent changes in brain structure and function, leading to the development of postnatal behavioral abnormalities. The rationale for the proposed research is that, once the pathogenesis of influenza virus-induced behavioral abnormalities is understood in mice, similar pathogenic mechanisms can be selectively sought for schizophrenia. We are uniquely prepared to undertake the proposed research, because we have succeeded in performing pilot studies, indicating that infection of mice on day 9 of pregnancy with a sublethal dose of human influenza virus causes abnormal corticogenesis and changes in levels of several important brain markers in postnatal life. Additionally, infection on day 9 of pregnancy leads to development of abnormal behavioral responses on prepulse inhibition in the affected adult mice. The central hypothesis will be tested and the objective of the application accomplished by pursuing three specific aims: 1) identify neuroanatomical molecular profiles for postnatal brain development that result from the effects of prenatal human influenza viral infection in mice using DMA microarray, 2) characterize morphometric abnormalities that are produced in the offspring following prenatal human influenza viral infection in mice by diffusion tensor microimaging and magnetic resonance volumetric studies, and 3) characterize behavioral abnormalities that are produced in mice by brain lesions that are comparable to those in patients with schizophrenia. The proposed work is innovative, because it capitalizes on our new animal model, which links a viral insult to abnormal brain development. It is our expectation that we will link the onset of post-viral structural changes in the brains of mice with the subsequent development of specific biochemical, behavioral and structural changes in affected animals. Such outcomes will be significant, because they are expected to provide a rational explanation for the epidemiological data supporting the link between human influenza viral infection, and the subsequent rise in births that lead to schizophrenia. In addition, it is expected that the results will provide clues that will lead to fundamental advances in our knowledge of the pathogenesis of schizophrenia and, therefore, of how it can be prevented and treated.
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