Behavioural testing as a method of assessing the progress of prion disease

Abstract

The Prion diseases are fatal neurodegenerative disorders that occur in humans and animals. The clinical signs do not become obviously apparent until the end stages of the disease and are usually followed by a rapid physical deterioration and death. Neuropathological studies show that prion disease is not an acute disease, but slowly establishes itself until neuronal death occurs. Behavioural changes that occur in mice inoculated with prion disease have been shown to be sensitive indicators of the early neurological degeneration that occurs in prion disease, and allows for the non-invasive assessment of the disease progression in its early stages. In this study formal behavioural testing has been used to assess the disease progression in ME7 infected mice under various experimental conditions. The role of the serotonergic system was investigated by inoculating mice with the ME7 scrapie agent directly into the locus of the serotonergic neurones of the Dorsal Raphe Nuclei (DRN). This resulted in a delay in the onset of the behavioural deficits when compared to mice inoculated with ME7 in the dorsal hippocampus. A tryptophan enhanced diet was used to elevate serotonin levels in the brain; however, this did not lead to any significant increases in serotonin levels or behavioural differences in the ME7 inoculated mice. The C57BL/Wld® mice have an autosomal dominant mutation that protects its axons and synapses from undergoing rapid Wallerian degeneration after axon injury. Wld® mutant mice were inoculated with ME7, to investigate whether the mutation would delay disease progression. However, it was found that the behavioural phenotype of the Wld® mice was markedly different to wt mice. Therefore, no clear conclusions could be drawn from the study. Aged mice were investigated to see whether the inflammation and neuropathogenesis, reported to occur as a natural course of ageing, increases vulnerability to prion infection. It was found that there was little difference in the aged mice (6-9 months) compared to young control mice (6-8 weeks) infected with prion disease. The use of behavioural testing can reveal signs of prion disease long before the clinical signs of the disease become apparent, and be used as sensitive indicators of the neuropathological changes that take place in prion diseased mice.

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