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

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Item Type:	Article
Title:	Stimulation of mGluR1/5 improves defective internalization of AMPA receptors in NPC1 mutant mouse
Creators Name:	Feng, X., Yang, F., Rabenstein, M., Wang, Z., Frech, M.J., Wree, A., Bräuer, A.U., Witt, M., Gläser, A., Hermann, A., 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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