Autism is a brain disorder characterized by abnormalities in social interaction, learning, and behavior. Although the basis for autism is unknown, both immune and infectious factors have been proposed to be important. One hypothesis is that prenatal or early postnatal infection results in aberrant brain development. This project will explore an animal model of autism based on CNS infection in early life. Borna disease virus (BDV) is a newly classified RNA virus that infects the CNS of warmblooded animals to cause disturbances of movement and behavior reminiscent of some aspects of autism and schizophrenia. Its host range includes most warmblooded species and there is accumulating evidence to suggest that humans may be infected; however, BDV has not been conclusively implicated in any human disease. Most previous work in BDV pathogenesis has focused on infected adult rodents and ungulates where dramatic disturbances in behavior, limbic circuitry, and monoamine neurotransmitter systems are associated with CNS inflammation, marked loss of brain mass, and gliosis. This project will focus instead on a neonatal rat infection model where BDV induces subtle disturbances of behavior, and hippocampal and cerebellar dysgenesis without robust inflammatory cell infiltration. Compelling similarities between sequelae of neonatal BDV infection and autism include stereotypic behaviors, abnormal responses to novel environments, abnormal taste preferences, growth delay, and hippocampal, cerebellar, and amygdalar pathology. Our objective will be to use this model to probe the mechanisms by which early viral infections alter CNS architecture and function.
Specific aims i nclude: (1) Characterize the behavioral, cognitive, and motoric dificits associated with early CNS infection. (2) Map the neurodevelopmental histopathology induced by neonatal infection using stereologic methods. (3) Evaluate the role of cytokines and reactive nitrogen intermediates as potential mediators of CNS damage following neonatal infection. (4) Determine how opoptosis contributes to the neuropathology observed after neonatal infection. (5) Analyze regional changes in neurotransmitter systems following neonatal infection.
