An infection-based model of neurodevelopmental damage

Abstract

Perinatal exposure to infectious agents and toxins is linked to the pathogenesis of neuropsychiatric disorders, but the mechanisms by which environmental 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. Architecture is markedly disrupted in hippocampus and cerebellum, with reduction in granule and Purkinje cell numbers. Neurons are lost predominantly by apoptosis, as supported by increased mRNA levels for pro-apoptotic products (Fas, caspase-1), decreased mRNA levels for the anti-apoptotic bcl-x, and in situ labeling of fragmented DNA. Although inflammatory infiltrates are observed transiently in frontal cortex, glial activation (microgliosis > astrocytosis) is prominent throughout the brain and persists for several weeks in concert with increased levels of proinflammatory cytokine mRNAs (interleukins 1␣, 1␤, and 6 and tumor necrosis factor ␣) and progressive hippocampal and cerebellar damage. The resemblance of these functional and neuropathologic abnormalities to human neurodevelopmental disorders suggests the utility of this model for defining cellular, biochemical, histologic, and functional outcomes of interactions of environmental influences with the developing central nervous system.

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

“…There is now good evidence that normal commensal bacteria can alter neurological and behavioral development (Foster et al, 2008) however, the presence of pathogenic microorganisms that can prematurely activate the innate immune system can also permanently alter adult immune function, physiology and behavior. Neonatal immune activation has been associated with such psychiatric disorders as Alzheimer's disease, schizophrenia, cerebral palsy and autism (Garnier et al, 2003;Hornig et al, 1999;Huleihel et al, 2004;Nelson and Willoughby, 2000;Rantakallio et al, 1997;Shi et al, 2003). Cytoarchitectural changes can also be seen in the adult animals exposed to immunogen as neonates such as enlargement of bilateral ventricles and alterations in axonal and dendritic arborization in the parietal cortex and substantia nigra (Fan et al, 2011).…”

Infectious and immune factors in neurodevelopmental damage

“…Other factors contributing to accelerated neuronal losses in neonatally infected animals may include reduction in mRNAs coding for neurotrophic factors and the anti-apoptotic product, bcl-x; and increases in mRNAs for pro-apoptotic products and proinflammatory cytokines. 2 Interestingly, in postmortem cerebellum and parietal cortex of individuals with autism, the anti-apoptotic factor, bcl2, is reduced, and in parietal cortex, the pro-apoptotic factor, p53, is increased, suggesting a biochemical basis for enhanced neuronal losses by apoptosis in autism. 6 However, changes in neurotrophic factor, apoptosis-related product, and cytokine gene expression in the neonatal rat model fail to fully explain the distribution and timing of cell death.…”

“…edu gyrus (DG), granule and Purkinje cells of cerebellum, and pyramidal neurons of layers V and VI of retrosplenial and cingulate cortex. 2,3 Infection alone is therefore an insufficient signal for cell loss, as many neuronal populations remain persistently infected without evident reduction of cell numbers. In addition, modest levels of apoptosis are seen in granule cells of cerebellum, yet these cells are spared from infection.…”

“…Infection of Lewis rat neonates with Borna disease virus (BDV), a noncytolytic, negativestrand RNA virus tropic for limbic and cerebellar circuitry and implicated in human neuropsychiatric disease, causes a spectrum of behavioral deficits reminiscent of autism without a substantial cell-mediated immune response, produces neuropathologic features reported in postmortem material of individuals with autism, and provides a model system for understanding neurodevelopmental disorder pathogenesis. 2,3 Neurobehavioral disturbances in this neonatal infection system that bear strong similarity to the impaired social interaction and atypical sensory and emotional responses pathognomonic of autism include disturbances of sensorimotor development and activity, 2 play, 4 emotional reactivity, 2 social communication (M Hornig and WI Lipkin, unpublished data), and spatial and aversive learning. 5 Intrigued by the possibility of distinguishing the more direct interactions of a microbe with the developing nervous system from those effects related to inflammation, we sought to elucidate the mechanisms contributing to CNS damage and dysfunction in the neonatal model.…”

“…2,3 Despite spread of virus throughout limbic circuitry and cerebellum by 2 weeks postinfection (pi), programmed cell death reaches a maximum at 4 weeks pi and is largely restricted to granule cells of dentate Correspondence: M Hornig, Emerging Diseases Lab, University of California, Irvine, CA 92697 4292, USA. E-mail: mhornig@uci.…”