Immune, infectious, and toxic factors introduced to susceptible hosts during pre- or postnatal development are proposed in the pathogenesis of some neurodevelopmental disorders, including autism, schizophrenia, affective disorders, attention deficit/hyperactivity disorder, antisocial personality disorder, and conduct disorder.1 The relative maturity of the nervous and immune systems at the time of exogenous agent exposure constrains host gene expression, and modifies the range of clinical outcomes that follow. To understand the pathogenesis of a specific neurodevelopmental disorder such as autism, factors determining age-sensitive vulnerability of selected neuronal populations to dysfunction or loss following introduction of microbes, toxins, or other environmental stimuli require definition. Infection of Lewis rat neonates with Borna disease virus (BDV), a noncytolytic, negative-strand 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of sensorimotor development and activity,2 play,4 emotional reactivity,2 social communication (M Hornig and WI Lipkin, unpublished data), and spatial and aversive learning.5 Intrigued by the possibility of distinguishing the more direct interactions of a microbe with the developing nervous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.
Previous studies in our laboratory suggest that neuronal losses following neonatal BDV infection occur by apoptosis.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 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. 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. Changes in neurotrophic factor gene expression are only observed in hippocampus at 4 weeks pi, possibly representing reduced synthesis following dropout of specific neuronal subsets, and cytokine and apoptosis-related product mRNA alterations wane after apoptosis peaks at 4 weeks but are still significant to 12 weeks pi, long after apoptosis has ceased. Furthermore, increases in serotonin levels are noted in hippocampus at days 217 and 28 pi (M Hornig, L Parsons, WI Lipkin, unpublished data)—changes which should serve to promote cell survival and prevent apoptosis. Serotonin is critical in establishment and maintenance of synaptic connections, yet persistent elevations of serotonin into the early post-weaning period (beginning approximately postnatal day 21) is associated with arrest of spine development.8 Alterations in serotonin may also modulate regional patterns of α-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptors, thereby contributing to plasticity and localized glutamatergic neurotransmission.9 Events leading to designation of specific subsets of infected neurons for death during this early period of brain plasticity remain unclear. AMPA and N-methyl-D-aspartate (NMDA) receptors appear to have contrasting, age-dependent effects on programmed cell death. Excitotoxic, glutamatergic injuries of newborn rat brain result in morphologic evidence of apoptotic neuronal death, approximating that which occurs during normal brain development;10 NMDA receptor blockade increases developmental elimination of neurons by apoptosis.11 The contribution of different glutamate receptor subtypes appears to be age-sensitive: in adult models of excitotoxic damage, blockade of NMDA receptors increases cell survival following glutamate exposure. Furthermore, transient AMPA receptor blockade protects developing chick brainstem auditory neurons from programmed cell death.12 We thus investigated whether viral infection affected excitatory synaptic connections and distribution of developmentally-regulated glutamate receptors, factors commonly thought to regulate cell survival during postnatal development.
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