Stimulation of mGluR1/5 Improves Defective Internalization of AMPA Receptors in NPC1 Mutant Mouse. (10th October 2019)

• Record Type: Journal Article
• Authors: Feng, Xiao; Yang, Fan; Rabenstein, Michael; Wang, Zhen; Frech, Moritz J; Wree, Andreas; Bräuer, Anja U; Witt, Martin; Gläser, Anne; Hermann, Andreas; Rolfs, Arndt; Luo, Jiankai
• Is Part Of: Cerebral cortex. Volume 30:Number 3(2020)
• Page Start: 1465
• Page End: 1480
• Publication Date: 2019-10-10
• Subjects: β-CD -- calcium imaging -- GluR2 -- lipid raft -- Niemann–Pick type C1 disease; Cerebral cortex -- Periodicals; Brain -- Periodicals; 612.825
• DOI: 10.1093/cercor/bhz179
• Languages: English
• ISSNs: 1047-3211

Abstract

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.