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Neurotransmitter metabolites, enzymes and receptors in experimental scrapie
Abstract:
A comprehensive study has been made of metabolites, enzymes and receptors for a variety of neurotransmitter systems in different parts of the CNS from mice affected with 139A scrapie. Studies were made at the early clinical stage so as to minimise secondary alterations in terminally sick mice. Even though histological lesions (vacuolation) are widespread in the CNS in this model of scrapie, no consistent neurochemical changes were found in mid- or anterior brain. In the cerebellum, the activity of glutamic acid decarboxylase was reduced and the binding of [3H]muscimol to gamma-aminobutyric acid receptors was increased. In the brain stem, the concentration of 5-hydroxyindoleacetic acid (5-HIAA) was increased and there was a reduced binding of appropriate ligands to serotonin and to muscarinic cholinergic receptors. In the spinal cord, the activity of choline acetyl transferase was reduced and the concentration of 5-HIAA was increased. The extent of these alterations was about 20-40% of control values. The specificity of these changes for a few neurotransmitter systems in hind brain and spinal cord raised the possibility of their being a primary cause of clinical disease and led us to study a different scrapie model. Present and published findings show that an increased concentration of 5-HIAA, some alterations in the binding properties of serotonin receptors and a decreased number of muscarinic receptor sites are common to both 139A scrapie in CW mice and 263K scrapie in hamsters.
Insights
Neurotransmitter changes in the hind brain and spinal cord, including increased 5-hydroxyindoleacetic acid (5-HIAA), suggest a primary role in scrapie pathogenesis. These findings are consistent across different scrapie models.
Area of Science:
- Neuroscience
- Prion Diseases
- Biochemistry
Background:
- Scrapie, a transmissible spongiform encephalopathy, affects the central nervous system (CNS).
- Early clinical stages of scrapie in mice (139A strain) were studied to identify primary neurochemical alterations.
- Histological lesions are widespread, but neurochemical changes were investigated in specific CNS regions.
Purpose of the Study:
- To investigate neurotransmitter system alterations in the early clinical stage of 139A scrapie in mice.
- To determine if observed neurochemical changes are specific to certain CNS regions or neurotransmitter systems.
- To compare findings with other scrapie models to identify common pathogenic mechanisms.
Main Methods:
- Measurement of metabolites, enzymes, and receptor binding in various CNS regions of scrapie-affected mice.
- Analysis of neurotransmitter systems including GABA, serotonin, and cholinergic pathways.
- Comparison of neurochemical data between affected mice and control groups.
Main Results:
- No consistent neurochemical changes were found in the mid- or anterior brain.
- In the cerebellum, reduced glutamic acid decarboxylase activity and increased gamma-aminobutyric acid (GABA) receptor binding were observed.
- In the brain stem and spinal cord, increased 5-hydroxyindoleacetic acid (5-HIAA) and altered serotonin and muscarinic cholinergic receptor binding were detected. Alterations ranged from 20-40% of control values.
Conclusions:
- Neurotransmitter system alterations, particularly in the hind brain and spinal cord, may be primary events in scrapie pathogenesis.
- Increased 5-HIAA, altered serotonin receptor binding, and decreased muscarinic receptor sites are common features in both 139A scrapie (mice) and 263K scrapie (hamsters).
- These conserved neurochemical changes suggest a shared mechanism underlying the clinical manifestations of different scrapie strains.