Maternal viral infection can increase the incidence of mental illness and cerebral palsy in the offspring. Such infections can also lead to miscarriage, premature and stillbirth and early neonatal mortality. We are utilizing a mouse model to examine the effects of maternal respiratory infection with influenza virus on fetal brain development. We find that the adult offspring of these mothers exhibit interesting behavioral abnormalities and striking responses to psychoactive drugs, as well as a neuropathological finding that is remarkably similar to that found in autism. (i) We have preliminary evidence that adult mice born to infected mothers exhibit a highly localized loss of Purkinje cells, similar to that observed in autistic brain. We will quantitate Purkinje cell density, as well as the width of the molecular layer in this and other parts of the cerebellum, in both adults and during development. (ii) It is possible that the infected mothers have altered maternal behavior, which could have lasting effects on the offspring. To investigate this, we will carry out cross-fostering experiments, in which the offspring of infected mothers are raised from birth by control mothers. These offspring will be tested behaviorally with the assays we have employed previously, and their brains will be examined by histology. (iii) As we have not detected viral infection of the fetus, it is possible that these morphological and behavioral abnormalities found in the offspring are due to the anti-viral inflammatory response mounted by the mother. Supporting this hypothesis are results of injecting pregnant mice with poly I:C, a double stranded RNA that causes an inflammatory response resembling that induced by viral infection. At least one of the behavioral abnormalities in the offspring can be elicited by this procedure, so further analysis of such offspring is merited. We also plan to test the effects of viral vaccination of pregnant mice on the behavior and neuropathology of the offspring. (iv) In parallel studies using cytokine knockout mice and cytokine adenoviral vectors, we are able to manipulate the inflammatory response in the brain and periphery. These and other strategies will be used to test whether manipulation of the mother's response to viral infection can prevent the development of brain abnormalities. Importantly, anti-cytokine strategies in influenza-infected mice have already proven effective in treating fever and lung inflammation. We will also use cytokine injections of non-infected mothers to help identify cytokines that may mediate the effects of maternal viral infection.
