Degeneration of Neuronal Processes after Infection with Pathogenic, but Not Attenuated, Rabies Viruses

Abstract

The structural alterations of neuronal processes in mice were investigated after the mice were infected with rabies virus (RV). Silver staining of infected brain sections showed severe destruction and disorganization of neuronal processes in mice infected with pathogenic RV but not with attenuated RV. However, neuronal bodies showed very little pathological changes. Electron microscopy revealed the disappearance of intracellular organelles, as well as the disappearance of synaptic structures and vesicles. Infection of primary neurons with pathogenic, but not attenuated, RV resulted in the destruction of neuronal processes and disappearance of microtubule-associated protein 2 and neurofilament immunoreactivity, which suggests that pathogenic RV causes degeneration of neuronal processes possibly by interrupting cytoskeletal integrity.Despite extensive investigation, the mechanism by which rabies virus (RV) infection causes neurological disease and death is still not completely understood (3). RV enters the peripheral nervous system at the bite site by binding to one or more specific neural receptors (14,22,25) with or without local replication (19,21). Once inside neurons, RV is spread by retrograde transport to the spinal cord and then to the brain (4, 12). Clinical signs include severe agitation, depression, hydrophobia, and paralysis followed by impaired consciousness and coma (9). Patients eventually die of circulatory insufficiency, cardiac arrest, and respiratory failure (9, 23). Despite the dramatic and severe clinical course, postmortem examination of rabies patients reveals only a few pathological lesions, such as cerebral edema (18). Inflammatory reactions and other histological lesions are mild with relatively little neuronal loss (15, 18). These observations led to the hypothesis that fatal rabies may result from neuronal dysfunction rather than neuronal damage (24).Studies of neuronal dysfunction have revealed electroencephalographic abnormalities, including the disappearance of rapid eye movement sleep and the development of pseudoperiodic facial myoclonus (6). Brain electrical activity terminated about 30 min before cardiac arrest, indicating that cerebral death in experimental rabies occurs prior to failure of vegetative functions (6, 7). RV infection of neurons also induces dysfunction of ion channels, for example, reduction in sodium channels and inward rectifier potassium channels (10, 11), which could prevent infected neurons from firing action potentials and generating synaptic potentials, resulting in functional impairment. Decreased binding of serotonin (particularly the subtype 5-HT 1D ) to its receptors has also been reported (2). Recent studies of the release of norepinephrine, dopamine, and serotonin in the hippocampi of rats infected with RV indicated that at the terminal stage of the disease, neurons are no longer capable of releasing neurotransmitters at the synaptic junctions (5). Hence, there is evidence of impaired release of neurotransmitters and binding of neurotransmitters to th...

Alteraciones de la morfología dendrítica neuronal en la corteza cerebral de ratones infectados con rabia: un estudio con la técnica de Golgi

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