An integrated, temporal study of the behavioural, electrophysiological and neuropathological consequences of murine prion disease

We have conducted an integrated study of ME7 prion disease by examining the electrophysiological and neuropathological features of hippocampal slices from behaviourally characterised C57Bl/6J mice 12, 14, 16, 18, 20 and 24 weeks after intracerebral micro-injection of ME7 or normal brain homogenate. We describe the pathogenesis of ME7 as a three-stage process. Stage one: PrP Sc deposition, synaptic pathology and abnormal synaptic plasticity. Stage two: Onset of behavioural changes, exemplified by an increase in open-field activity, enhancement of the slow AHP and development of vacuolation. Membrane depolarisation is also an early feature, but its exact timing remains to be confirmed. Stage three: Clinical disease, substantial neurodegeneration and further disruption of the action potential profile. We suggest that the mechanisms underlying the electrophysiological changes of Stages one and two may provide novel approaches to treatment of prion disease, and that those seen in Stage three may be relevant to neurodegenerative diseases more generally.