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Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity

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mGluR1/5 inhibition rescues prion neurotoxicity in organotypic slice cultures.

(A-B) Treatment with the mGluR5 inhibitor (MPEP) rescued neurodegeneration in tga20 RML6-treated COCS. (A) Fluorescence micrographs of tga20 COCS. RML6-induced ablation of the cerebellar granular layer (CGL) was significantly ameliorated by the mGluR5 inhibitor, MPEP. All scale bars: 500μm. (B) NeuN coverage in tga20 COCS exposed to RML6 or NBH and treated with MPEP at 21–45 days post inoculation (dpi), expressed as percentage of NBH samples. Each dot represents a pool of 4–10 slices cultured in the same well. Data points are mean ± s.d.; one-way ANOVA followed by Dunnett’s post-hoc test. (C-D) Treatment with the mGluR5 inhibitor AFQ056 (mavoglurant) also rescued neurodegeneration in tga20 RML6-treated COCS (experimental conditions as in panels A-B). (E-F) Treatment with the mGluR5 inhibitor (MPEP) rescued neurodegeneration in tga20 RML6-treated HOCS. (E) Fluorescence micrographs of tga20 HOCS, showing ablation of hippocampal neurons induced by RML6 infection (middle), that is significantly ameliorated by addition of the IC50 concentration of MPEP (36nM, 21–45 dpi, right). (F) Morphometry of the experiment shown in panel E. (G) Treatment with the mGluR1 inhibitor (YM202074) rescued neurodegeneration in tga20 RML6-treated COCS. Experimental conditions were the same as in the panels above. (H) Morphometry of the experiment shown in panel G; *: P < 0.05, **: P < 0.01, ***: P < 0.001; For (A), (C), (E) and (G) panels: Scale bar is 500μm.

Fig 1

doi: https://doi.org/10.1371/journal.ppat.1006733.g001