Molecular mechanisms of neurodegeneration in a model of perinatal viral infection

Borna disease virus (BDV) is a neurotropic RNA virus that causes persistent infection in the central nervous system of warm-blooded animals. Rats, infected with BDV as neonates (Neonatal Borna Disease: NBD), develop abnormalities in behavior and neuroanatomical disturbances, in the absence of immunopathological changes associated with adult infections. Although BDV's replication is noncytolytic in vitro, neonatal infection results in apoptotic damage to select neural populations, including hippocampal dentate gyrus granule cells, cerebellar Purkinje cells, and cortical neurons. The molecular pathways mediating neural death in NBD rats have not been defined. In this dissertation we address mechanisms of neurodegeneration in NBD rats, with the objective of identifying host response elements that trigger neuronal demise in the wake of neonatal viral infection.; Our findings suggest that zinc homeostatic control mechanisms are specifically altered in the hippocampus of NBD rats. Enhanced astrocytic expression of metallothioneins, loss of zinc transporter 3 expression from mossy fibers, accumulation of zinc in degenerating dentate gyrus granule cells, enhanced poly(ADP-ribose) polymerase expression, and neuroplastic changes in the form of mossy fiber sprouting likely contribute to zinc redistribution and toxicity in dentate gyrus granule cells in NBD.; Neurodegeneration in other brain regions was not associated with zinc disturbances in NBD. Endoplasmic reticulum (ER) stress, assessed by cellular gene expression and activation of the unfolded protein response, was identified in degenerating neurons and astrocytes in NBD. The ER stress-induced pro-apoptotic molecule, Chop, was increased in degenerating Purkinje neurons in the absence of compensatory ER survival molecules. In contrast, astrocytes which are infected by BDV, but do not die in NBD, expressed both pro-apoptotic and survival molecules. Thus, the balance between these ER signals may determine cell fate in NBD.; Cerebellar damage in animal models of disease is often characterized by patterned degeneration of Purkinje cell subsets. In NBD, we found that Purkinje neurons expressing high levels of aldolase C and the excitatory amino acid transporter 4 are provided preferential, region-specific protection during early stages of NBD.{09}These findings suggest that temporal and spatial differences in postnatal cerebellar development may be contributing determinants of Purkinje cell sensitivity to infection-induced insults.