EARLY UNSUSPECTED NEURON AND AXON TERMINAL LOSS IN SCRAPIE-INFECTED MICE REVEALED BY MORPHOMETRY AND IMMUNOCYTOCHEMISTRY

Neuronal loss is often quoted as an element of the pathology of the tr ansmissible spongiform encephalopathies, but few data are published. T o determine whether neuronal loss is a salient feature of murine scrap ie, and whether there is a relationship with the other hallmark lesion s of scrapie we compared the numbers of neurons, severity of vacuolati on, axonal bouton density and distribution of prion protein (PrP) in t he dorsal lateral geniculate nucleus (dLGN) following intraocular infe ction of C57BL/FaBtDk mice with ME7 scrapie. This route of infection l imits the initial spread of infection to the retinal efferents, thus d irecting infectivity and subsequent pathological changes to the dLGN w hich is a major projection of the optic nerve. Morphometric assessment of neuron number in the dLGN was made on semi-serial sections from fi ve infected and five normal brain injected controls at four 50-day int ervals during the incubation period, and on terminally affected mice. The number of neurons decreased from around 20 000 at 50 days to under 1000 in the terminal group. Significant loss was identified in indivi dual mice at 150 days post-infection, coincident with the onset of vac uolation; neuron number was found to have an inverse relationship to t he severity of vacuolation. Axonal boutons in the dLGN (demonstrated b y synaptophysin immunolabelling) were reduced at 200 days, and virtual ly absent in terminal mice. The intensity of PrP immunostaining progre ssively increased from 150 days, and in a separate experiment PrP was detected from 175 days by polyacrylamide gel electrophoresis of brain extracts. These results show that early neuronal loss is a significant feature of experimental scrapie infection, and the possible mechanism s of this degeneration are discussed.