期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 63, 期 8, 页码 882-899出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnen/63.8.882
关键词
gamma-aminobutyric acid; GABA; neurodegeneration; prion; PrPSc; synapses; synaptosomes
资金
- NIA NIH HHS [AG02132, AG021601, AG10770] Funding Source: Medline
Loss of the GABAergic system of neurons has been reported to be the first detectable neuropathological change in prion diseases, which features the accumulation of an aberrant isoform of the prion protein (PrPsc). To determine the timing of GABAergic system dysfunction and degeneration and its relationship to PrPsc accumulation during the course of prion disease in Syrian hamsters, we applied 3 approaches: i) quantifying GABA-immunopositive neurons and their processes by light and electron microscopy to test for selective loss; ii) measuring evoked [H-3]-GABA release from synaptosomes to test for functional abnormalities; and iii) determining the kinetics of PrPsc, accumulation in subcellular fractions to correlate it with GABAergic dysfunction. At the terminal stages of disease, we found a significant increase in the number of GABA-positive and -negative presynaptic boutons with abnormally aggregated synaptic vesicles. At the same stage, we also found an equal degree of GABA-immunopositive and -immunonegative presynaptic bouton loss. In contrast, GABA-positive neocortical cell bodies increased, based on stereologic estimates in the terminal stage of scrapie. In the context of these abnormalities, evoked release of [H-3]-GABA from cortical and thalamic synaptosomes was significantly decreased, which correlated well with the accumulation of PrPsc in synaptosomes and cell membrane fractions.
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