A-C With this model we propose that in the wt situation LTP induction promotes the synthesis of NPC1, which enhances the surface delivery of CYP46A1. While the exact mechanism mediating this effect remains to be determined we propose NPC1 could reach the plasma membrane from the endolysosomal compartment and act as a tether between ER and the plasma membrane facilitating the surface delivery of CYP46A1. This allows cholesterol hydroxylation and release that is necessary for AMPAR plasma membrane delivery, LTP progression and thus learning and memory. The NPC1 mutation D1005G enhances the protein degradation in synapses preventing LTP-induced NPC1 increase. This hampers CYP46A1 surface expression and cholesterol reduction resulting in less AMPAR delivery to the plasma membrane and impaired learning and memory. The use of EFV activates CYP46A1 restoring cholesterol reduction, AMPAR surface delivery, LTP and learning and memory abilities. 