Enhanced mGluR₅ intracellular activity causes psychiatric alterations in Niemann Pick type C disease

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 mGluR₅ 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 mGluR₅ distribution in NPC1-deficient neurons. Intracellular accumulation of mGluR₅ 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 mGluR₅ agonists, respectively. Oral treatment with the mGluR₅ antagonist 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP) reduced mGluR-LTD and ameliorated psychiatric anomalies in the Npc1^nmf164 mice. Increased neuronal mGluR₅ levels were found in an NPC patient. These results implicate mGluR₅ alterations in NPC psychiatric condition and provide a new therapeutic strategy that might help patients suffering from this devastating disease.