An integrated, temporal study of the behavioural, electrophysiological and neuropathological consequences of murine prion disease
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Published on: April 13, 2017
Z Chiti1, O M Knutsen, S Betmouni
1MRC Centre for Synaptic Plasticity, University of Bristol, Bristol, UK. z.chiti@bris.ac.uk
Abstract:
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: PrPSc 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.
Insights
This study details the three-stage progression of ME7 prion disease in mice, linking electrophysiological changes to neuropathology and behavioral shifts. Early electrophysiological alterations may offer novel therapeutic targets for prion and other neurodegenerative diseases.
Area of Science:
- Neuroscience
- Pathology
- Prion Disease Research
Background:
- ME7 prion disease is a transmissible spongiform encephalopathy affecting the brain.
- Understanding its progression is crucial for developing effective treatments.
- Previous studies have focused on specific aspects, but an integrated view is lacking.
Purpose of the Study:
- To investigate the electrophysiological and neuropathological progression of ME7 prion disease.
- To characterize the pathogenesis of ME7 prion disease as a multi-stage process.
- To identify potential therapeutic targets based on early electrophysiological changes.
Main Methods:
- Integrated study of electrophysiological and neuropathological features.
- Analysis of hippocampal slices from C57Bl/6J mice at multiple time points post-ME7 injection.
- Behavioral characterization of mice throughout the disease course.
Main Results:
- ME7 prion disease progresses in three distinct stages: PrPSc deposition and synaptic pathology, onset of behavioral changes with electrophysiological alterations, and clinical disease with neurodegeneration.
- Early electrophysiological changes, including abnormal synaptic plasticity and altered action potential profiles, correlate with disease progression.
- Specific electrophysiological changes in early stages (Stage One and Two) are identified.
Conclusions:
- The pathogenesis of ME7 prion disease can be described as a three-stage process.
- Electrophysiological changes in the early stages of prion disease may offer novel therapeutic strategies.
- Electrophysiological alterations observed in late-stage disease could be relevant to neurodegenerative diseases broadly.
