M. V. Pletnikov*1, D. Dietz*1, S.A. Rubin*2, T.H. Moran*1 and K.M. Carbone1,2,3. Departments of 1Psychiatry and 3Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205. 2LPRVD/DVP/OVRR/CBER/FDA, Bethesda, MD 20892.
Over the past ten years, we have developed and characterized an animal model of autism using neonatal Borna disease infection (BDV) as a unique experimental teratogen to produce selective neuroanatomical, neurochemcal, neuroimmunological and behavioral deficits consistent with several key features of autism. Here, we present data from a multidisciplinary study of the effects of genetic background on BDV-induced brain pathology (e.g., hippocampus, cerebellum and cortex), monoamine alterations (e.g., serotonin), behavioral deficits (e.g., hyper-reactivity), and responses to pharmacological treatments (e.g., fluoxetine) in developing and adult Lewis and Fisher344 inbred rat strains.
While no effects of genetic background were observed in neonatal BDV infection-induced inhibition of the weight gain and viral load in brains of Fisher344 and Lewis rats throughout the postnatal period, and quantitative stereological analysis revealed comparable BDV-associated cell loss in the dentate gyrus of the hippocampus in two rat strains at different time points post infection (p.i.), histopathological examination of BDV-induced cortical injury indicated a more severe damage in BDV-infected Fisher344 rats compared to BDV-infected Lewis at day 30 p.i. HPLC and receptor autoradiography studies indicated regional and strain-specific monoamine alterations in tissue content, turnover and density of post- and presynaptic receptors in developing and adult BDV-infected Lewis and Fisher344 rats. The observed effects of genetic background on BDV-associated neurochemical alterations might have led to strain-specific deficits in prepulse inhibition of the acoustic startle and hyper-reactivity to novelty. Moreover, BDV-associated serotonin disturbances appeared to be linked to differential sensitivity to pharmacological treatment in developing and adult Lewis and Fisher344 rats.
The present findings seem to indicate the value of the BDV animal model of autism for studying the pathogenesis of autism-like neurodevelopmental damage and for pre-clinical testing of novel treatments.
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