ABSTRACT: The molecular mechanism underlying muscarinic acetylcholine receptor-dependent LTD (mAChR-LTD) in the hippocampus is less studied. In a recent study, a novel mechanism is described. The induction of mAChR-LTD required the activation of protein tyrosine phosphatase (PTP), and the expression was mediated by AMPA receptor endocytosis via interactions between GluA2, GRIP and liprin-alpha. The hook-up of these proteins may result in the recruitment of leukocyte common antigen-related receptor (LAR), a PTP that is known to be involved in AMPA receptor trafficking. Interestingly, the similar molecular interaction cannot be applied to mGluR-LTD, despite the fact that the same G-protein involved in LTD is activated by both mAChR and mGluR. This discovery provides key molecular insights for cholinergic dependent cognitive function, and mAChR-LTD can serve as a useful cellular model for studying the roles of cholinergic mechanism in learning and memory.