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Marked decrease of neuropeptide Y Y2 receptor binding sites in the hippocampus in murine prion disease
M Diez1, J Koistinaho, S J Dearmond
1Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Abstract:
Using autoradiographic binding methodology with monoiodinated peptide YY together with the agonists neuropeptide Y (NPY) and NPY (13-36), as well as in situ hybridization with oligonucleotide probes complementary to the NPY Y2 receptor (Y2-R) mRNA, we have studied whether or not intracerebral prion inoculation affects Y2-Rs in male CD-1 mice. Monoiodinated peptide YY binding, mainly representing Y2-Rs, was down-regulated by 85% in the CA1 strata oriens and radiatum and by 50-65% in the CA3 stratum oriens 110-140 days postinoculation. In the CA3 stratum radiatum, where the mossy fibers from the dentate granule cells project, there was a significant decrease in PYY binding at 110-120 days. Y2-R mRNA, moderately expressed both in the CA1 and CA3 pyramidal cell layers and the granule cell layer in the dentate gyrus, showed a slight, but not significant, decrease in CA3 neurons 130 days postinoculation. The results indicate that the accumulation of the scrapie prion protein in the CA1-3 region strongly inhibits NPY binding at the Y2-Rs, which, however, is only marginally due to reduced Y2-R mRNA expression. The loss of the ability of NPY to bind to inhibitory Y2-Rs may cause dysfunction of hippocampal circuits and may contribute to the clinical symptoms in mouse scrapie.
Insights
Prion disease significantly reduces neuropeptide Y Y2 receptors (Y2-Rs) in mouse hippocampus, impairing NPY binding. This dysfunction may contribute to clinical symptoms in scrapie.
Area of Science:
- Neuroscience
- Prion Disease Research
- Molecular Biology
Background:
- Neuropeptide Y (NPY) plays a crucial role in regulating neuronal function.
- NPY Y2 receptors (Y2-Rs) are implicated in various neurological processes.
- Prion diseases, like scrapie, cause neurodegeneration and synaptic dysfunction.
Purpose of the Study:
- To investigate the impact of intracerebral prion inoculation on Y2-Rs in the mouse hippocampus.
- To determine if prion accumulation affects Y2-R expression and function.
Main Methods:
- Autoradiographic binding assays using monoiodinated peptide YY (PYY) and NPY agonists.
- In situ hybridization to quantify Y2-R mRNA levels.
- Study conducted in male CD-1 mice inoculated intracerebrally with prions.
Main Results:
- Significant down-regulation of PYY binding (85% in CA1, 50-65% in CA3) observed 110-140 days postinoculation.
- Y2-R mRNA levels showed a slight, non-significant decrease in CA3 neurons.
- Prion accumulation strongly inhibited NPY binding to Y2-Rs, primarily independent of mRNA levels.
Conclusions:
- Scrapie prion protein accumulation in the hippocampus severely impairs NPY binding to Y2-Rs.
- Reduced Y2-R function, rather than decreased receptor expression, likely contributes to hippocampal circuit dysfunction.
- This Y2-R dysfunction may play a role in the clinical manifestations of mouse scrapie.