Targeting cellular prion protein reverses early coanitive deficits and neurophysiological dysfunction in prion-infected mice

Currently, no treatment can prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that targeting endogenous neuronal prion protein (PrPc) (the precursor of its disease-associated isoform, PrPsc) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss. We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology. Remarkably, these behavioral and synaptic impairments recover when neuronal PrPc is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrPsc deposits accumulate and recover rapidly after PrPc depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrPsc. These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.