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Loss of Perineuronal Net in ME7 Prion Disease
Sarah L Franklin1, Seth Love, J Richard T Greene
1MRC Centre for Synaptic Plasticity, University of Bristol, Bristol, United Kingdom.
Abstract:
Microglial activation and behavioral abnormalities occur before neuronal loss in experimental murine prion disease; the behavioral changes coincide with a reduction in synaptic plasticity. Because synaptic plasticity depends on an intact perineuronal net (PN), a specialized extracellular matrix that surrounds parvalbumin (PV)-positive GABAergic (gamma-aminobutyric acid [GABA]) inhibitory interneurons, we investigated the temporal relationships between microglial activation and loss of PN and PV-positive neurons in ME7 murine prion disease. Anesthetized C57Bl/6J mice received bilateral intracerebral microinjections of ME7-infected or normal brain homogenate into the dorsal hippocampus. Microglial activation, PrP accumulation, the number of PV-positive interneurons, and Wisteria floribunda agglutinin-positive neurons (i.e. those with an intact PN) were assessed in the ventral CA1 and subiculum at 4, 8, 12, 16, and 20 weeks postinjection. Hippocampal areas and total neuron numbers in the ventral CA1 and subiculum were also determined. Loss of PN coincided with early microglial activation and with a reduction in synaptic plasticity. No significant loss of PV-positive interneurons was observed. Our findings suggest that the substrate of the earliest synaptic and behavioral abnormalities in murine prion disease may be inflammatory microglia-mediated degradation of the PN.
Insights
Early microglial activation in prion disease degrades the perineuronal net (PN), impacting synaptic plasticity before neuron loss. This suggests PN degradation contributes to early behavioral changes in this neurological condition.
Area of Science:
- Neuroscience
- Neuroimmunology
- Prion Disease Research
Background:
- Microglial activation and behavioral changes precede neuronal loss in murine prion disease.
- Synaptic plasticity deficits correlate with behavioral abnormalities.
- Perineuronal nets (PN) are crucial for synaptic plasticity, surrounding parvalbumin (PV)-positive inhibitory interneurons.
Purpose of the Study:
- To investigate the temporal relationship between microglial activation and the loss of PN and PV-positive neurons in ME7 murine prion disease.
- To understand the role of PN degradation in early synaptic and behavioral abnormalities.
Main Methods:
- ME7-infected or normal brain homogenate was stereotaxically injected into the hippocampus of C57Bl/6J mice.
- Microglial activation, PrP accumulation, PV-positive interneurons, and Wisteria floribunda agglutinin (WFA)-positive neurons (indicating intact PN) were assessed at multiple time points.
- Hippocampal area and total neuron numbers were also quantified.
Main Results:
- Loss of PN was observed to coincide with early microglial activation.
- A reduction in synaptic plasticity was noted concurrently with PN loss.
- No significant loss of PV-positive interneurons was detected during the study period.
Conclusions:
- The earliest synaptic and behavioral abnormalities in murine prion disease may stem from inflammatory microglia-mediated degradation of the perineuronal net (PN).
- This degradation occurs independently of significant loss of PV-positive interneurons.
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