Targeting Cellular Prion Protein Reverses Early Cognitive Deficits and Neurophysiological Dysfunction in Prion-Infected Mice

• Published in: Neuron (Cambridge, Mass.) Vol. 53; no. 3; pp. 325 - 335
• Main Authors: Mallucci, Giovanna R., White, Melanie D., Farmer, Michael, Dickinson, Andrew, Khatun, Husna, Powell, Andrew D., Brandner, Sebastian, Jefferys, John G.R., Collinge, John
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2007; Elsevier Limited
• Subjects: Animals; Axons - physiology; Behavior; Behavior, Animal - physiology; Brain - pathology; Brain research; Cognition Disorders - prevention & control; Cognition Disorders - psychology; Discrimination, Psychological - physiology; Electrophysiology; Hippocampus - pathology; HUMDISEASE; Immunohistochemistry; Infections; Long-Term Potentiation - physiology; Memory; Memory Disorders - etiology; Memory Disorders - psychology; Mice; Mice, Transgenic; Motor Activity - physiology; Muscle, Skeletal - physiology; Nesting Behavior - physiology; Pathology; Prion Diseases - genetics; Prion Diseases - pathology; Prion Diseases - psychology; Prions; PrPC Proteins - genetics; Psychomotor Performance - physiology; Reverse Transcriptase Polymerase Chain Reaction; Synapses - pathology; Synapses - physiology; SYSNEURO; Visual Perception - physiology; SYSNEURO; HUMDISEASE
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2007.01.005

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.