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Enhanced mGluR5 intracellular activity causes psychiatric alterations in Niemann Pick type C disease
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Enhanced mGluR5 intracellular activity causes psychiatric alterations in Niemann Pick type C disease
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Journal Article
Enhanced mGluR5 intracellular activity causes psychiatric alterations in Niemann Pick type C disease
2024
Overview
Niemann-Pick disease Type C (NPC) is caused by mutations in the cholesterol transport protein NPC1 leading to the endolysosomal accumulation of the lipid and to psychiatric alterations. Using an NPC mouse model (Npc1
nmf164
) we show aberrant mGluR
5
lysosomal accumulation and reduction at plasma membrane in NPC1 deficient neurons. This phenotype was induced in wild-type (wt) neurons by genetic and pharmacological NPC1 silencing. Extraction of cholesterol normalized mGluR
5
distribution in NPC1-deficient neurons. Intracellular accumulation of mGluR
5
was functionally active leading to enhanced mGluR-dependent long-term depression (mGluR-LTD) in Npc1
nmf164
hippocampal slices. mGluR-LTD was lower or higher in Npc1
nmf164
slices compared with wt when stimulated with non-membrane-permeable or membrane-permeable mGluR
5
agonists, respectively. Oral treatment with the mGluR
5
antagonist 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1
H
-imidazol-4-yl)ethynyl)pyridine (CTEP) reduced mGluR-LTD and ameliorated psychiatric anomalies in the Npc1
nmf164
mice. Increased neuronal mGluR
5
levels were found in an NPC patient. These results implicate mGluR
5
alterations in NPC psychiatric condition and provide a new therapeutic strategy that might help patients suffering from this devastating disease.
