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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 (PrP(C)) (the precursor of its disease-associated isoform, PrP(Sc)) 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 PrP(C) 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 PrP(Sc) deposits accumulate and recover rapidly after PrP(C) depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrP(Sc). These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.

Original publication

DOI

10.1016/j.neuron.2007.01.005

Type

Journal article

Journal

Neuron

Publication Date

01/02/2007

Volume

53

Pages

325 - 335

Keywords

Animals, Axons, Behavior, Animal, Brain, Cognition Disorders, Discrimination (Psychology), Electrophysiology, Hippocampus, Immunohistochemistry, Long-Term Potentiation, Memory Disorders, Mice, Mice, Transgenic, Motor Activity, Muscle, Skeletal, Nesting Behavior, PrPC Proteins, Prion Diseases, Psychomotor Performance, Reverse Transcriptase Polymerase Chain Reaction, Synapses, Visual Perception