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Synaptic changes characterize early behavioural signs in the ME7 model of murine prion disease
C Cunningham1, R Deacon, H Wells
1CNS Inflammation Group, Southampton Neuroscience Group, School of Biological Sciences, University of Southampton, Southampton SO16 7PX, UK. C.Cunningham@soton.ac.uk
Abstract:
Prion diseases are fatal, chronic neurodegenerative diseases of mammals, characterized by amyloid deposition, astrogliosis, microglial activation, tissue vacuolation and neuronal loss. In the ME7 model of prion disease in the C57BL/6 J mouse, we have shown previously that these animals display behavioural changes that indicate the onset of neuronal dysfunction. The current study examines the neuropathological correlates of these early behavioural changes. After injection of ME7-infected homogenate into the dorsal hippocampus, we found statistically significant impairment of burrowing, nesting and glucose consumption, and increased open field activity at 13 weeks. At this time, microglia activation and PrPSc deposition was visible selectively throughout the limbic system, including the hippocampus, entorhinal cortex, medial and lateral septum, mamillary bodies, dorsal thalamus and, to a lesser degree, in regions of the brainstem. No increase in apoptosis or neuronal cell loss was detectable at this time, while in animals at 19 weeks postinjection there was 40% neuronal loss from CA1. There was a statistically significant reduction in synaptophysin staining in the stratum radiatum of the CA1 at 13 weeks indicating loss of presynaptic terminals. Damage to the dorsal hippocampus is known to disrupt burrowing and nesting behaviour. We have demonstrated a neuropathological correlate of an early behavioural deficit in prion disease and suggest that this should allow insights into the first steps of the neuropathogenesis of prion diseases.
Insights
Early behavioral changes in prion disease models are linked to specific neuropathological changes. This study identifies early microglial activation and synaptic terminal loss in the hippocampus, preceding significant neuronal death.
Area of Science:
- Neuroscience
- Pathology
Background:
- Prion diseases are fatal neurodegenerative disorders in mammals.
- Characterized by amyloid plaques, inflammation, and neuronal loss.
- Early detection of neuropathological changes is crucial for understanding disease progression.
Purpose of the Study:
- To investigate the neuropathological basis of early behavioral deficits in a mouse model of prion disease.
- To correlate behavioral changes with specific molecular and cellular alterations in the brain.
Main Methods:
- Utilized the ME7 model of prion disease in C57BL/6 J mice.
- Injected ME7-infected homogenate into the dorsal hippocampus.
- Assessed behavioral changes (burrowing, nesting, open field activity, glucose consumption) and neuropathology (microglia activation, PrPSc deposition, apoptosis, neuronal loss, synaptophysin staining) at 13 and 19 weeks post-injection.
Main Results:
- At 13 weeks, mice showed impaired burrowing, nesting, reduced glucose consumption, and increased open field activity.
- Microglia activation and PrPSc deposition were observed in the limbic system, including the hippocampus.
- A reduction in presynaptic terminals (synaptophysin staining) in CA1 was detected at 13 weeks, preceding significant neuronal loss (40% in CA1 at 19 weeks).
Conclusions:
- Demonstrated a direct neuropathological correlate for early behavioral deficits in prion disease.
- Suggests that early synaptic terminal loss and microglial activation in the hippocampus are key events in prion disease pathogenesis.
- Provides insights into the initial stages of neurodegeneration in prion diseases.