0896-62734962006Mar16NeuronTargeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression.845860845-60Cerebellar long-term depression (LTD) is a major form of synaptic plasticity that is thought to be critical for certain types of motor learning. Phosphorylation of the AMPA receptor subunit GluR2 on serine-880 as well as interaction of GluR2 with PICK1 have been suggested to contribute to the endocytic removal of postsynaptic AMPA receptors during LTD. Here, we show that targeted mutation of PICK1, the GluR2 C-terminal PDZ ligand, or the GluR2 PKC phosphorylation site eliminates cerebellar LTD in mice. LTD can be rescued in cerebellar cultures from mice lacking PICK1 by transfection of wild-type PICK1 but not by a PDZ mutant or a BAR domain mutant deficient in lipid binding, indicating the importance of these domains in PICK1 function. These results demonstrate that PICK1-GluR2 PDZ-based interactions and GluR2 phosphorylation are required for LTD expression in the cerebellum.SteinbergJordan PJPHoward Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.TakamiyaKogoKShenYingYXiaJunJRubioMaria EMEYuSandySJinWenyingWThomasGareth MGMLindenDavid JDJHuganirRichard LRLengR01 NS036715NSNINDS NIH HHSUnited StatesNS 36715NSNINDS NIH HHSUnited StatesMH51106MHNIMH NIH HHSUnited StatesComparative StudyJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't