Item Type: | Article |
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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 |
ISSN: | 1047-3211 |
Publisher: | Oxford University Press |
Volume: | 30 |
Number: | 3 |
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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