An infection-based model of neurodevelopmental damage

Perinatal exposure to infectious agents and toxins is linked to the pathoge nesis of neuropsychiatric disorders, but the mechanisms by which environmen tal triggers interact with developing immune and neural elements to create neurodevelopmental disturbances are poorly understood. We describe a model for investigating disorders of central nervous system development based on neonatal rat infection with Borna disease virus, a neurotropic noncytolytic RNA virus. Infection results in abnormal righting reflexes, hyperactivity. inhibition of open-field exploration, and stereotypic behaviors. Architect ure is markedly disrupted in hippocampus and cerebellum, with reduction in granule and Purkinje cell numbers. Neurons are lost predominantly by apopto sis, as supported by increased mRNA levels for pro-apoptotic products (Fas, caspase-1), decreased mRNA levels for the anti-apoptotic bcl-x, and in sit u labeling of fragmented DNA. Although inflammatory infiltrates are observe d transiently in frontal cortex, glial activation (microgliosis z astrocyto sis) is prominent throughout the brain and persists for several weeks in co ncert with increased levels of proinflammatory cytokine mRNAs (interleukins 1 alpha, 1 beta, and 6 and tumor necrosis factor alpha) and progressive hi ppocampal and cerebellar damage. The resemblance of these functional and ne uropathologic abnormalities to human neurodevelopmental disorders suggests the utility of this model for defining cellular, biochemical, histologic, a nd functional outcomes of interactions of environmental influences with the developing central nervous system.