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Stimulation of mGluR1/5 improves defective internalization of AMPA receptors in NPC1 mutant mouse

Item Type:Article
Title:Stimulation of mGluR1/5 improves defective internalization of AMPA receptors in NPC1 mutant mouse
Creators Name:Feng, X. and Yang, F. and Rabenstein, M. and Wang, Z. and Frech, M.J. and Wree, A. and Bräuer, A.U. and Witt, M. and Gläser, A. and Hermann, A. and Rolfs, A. and Luo, J.
Abstract:Niemann-Pick type C1 (NPC1) disease is characterized by neurodegeneration caused by cholesterol accumulation in the late endosome/lysosome. In this study, a defective basal and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-stimulated internalization of GluR2-containing AMPA receptors in NPC1-/- cortical neurons was detected. Our results show that the amount of cholesterol and group I metabotropic glutamate receptors (mGluR1/5) in lipid rafts of NPC1-/- cortical tissue and neurons are decreased and their downstream signals of p-ERK are defective, which are restored by a rebalance of cholesterol homeostasis through β-cyclodextrin (β-CD) treatment. Application of 3,5-dihydroxyphenylglycine (DHPG)-a mGluR1/5 agonist-and β-CD markedly increases the internalization of AMPA receptors and decreases over-influx of calcium in NPC1-/- neurons, respectively. Furthermore, the defective phosphorylated GluR2 and protein kinase C signals are ameliorated by the treatment with DHPG and β-CD, respectively, suggesting an involvement of them in internalization dysfunction. Taken together, our data imply that abnormal internalization of AMPA receptors is a critical mechanism for neuronal dysfunction and the correction of dysfunctional mGluR1/5 is a potential therapeutic strategy for NPC1 disease.
Keywords:β-CD, Calcium Imaging, GluR2, Lipid Raft, Niemann-Pick Type C1 Disease, Animals, Mice
Source:Cerebral Cortex
Publisher:Oxford University Press
Page Range:1465-1480
Date:March 2020
Official Publication:https://doi.org/10.1093/cercor/bhz179
PubMed:View item in PubMed

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