Synapse loss associated with abnormal PrP precedes neuronal degeneration in the scrapie-infected murine hippocampus

Numbers of neurones, synapses and axon terminals were quantified in a murin e scrapie model with severe hippocampal pyramidal cell loss, in which defin ite clinical scrapie is evident from 226 days post-infection (dpi) and deat h occurs around 250 dpi. Disease-specific PrP accumulations were first seen at 70 dpi (28% of the incubation period (IP)) in thalamus and as sparse fo ci within the stratum pyramidale of CA1. By 98 dpi (39% IP), PrP was seen i n the stratum radiatum and was found at later stages throughout all levels of the hippocampus. At the ultrastructural level in the stratum radiatum of CA1, a decrease in the numbers of simple synapses from 84 dpi (34% IP) and in perforated synapses from 98 dpi (42% IP) was found using an unbiased st ereological method, the disector analysis. Degeneration of axon terminals w as found from 98 dpi (39% IP) onwards. Neuronal loss was detected in CA1 fr om 180 dpi (72% IP). The results suggest that the fundamental lesion in the hippocampus of ME7-infected mice is associated with PrP release from CA1 p yramidal neurones, which perturbs synaptic function and leads to degenerati on of preterminal axons, and that subsequent pathological changes including neurone loss are sequelae to this initial insult.