Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression.
Cerebellar 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.
Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
Jordan P
JP
Steinberg
Kogo
K
Takamiya
Ying
Y
Shen
Jun
J
Xia
Maria E
ME
Rubio
Sandy
S
Yu
Wenying
W
Jin
Gareth M
GM
Thomas
David J
DJ
Linden
Richard L
RL
Huganir
D000367:Age Factors; D000409:Alanine / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008055:Lipids / Q000032:analysis; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D036881:Long-Term Synaptic Depression / Q000235:genetics*; D008239:Lysine / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016253:Microscopy, Immunoelectron / Q000379:methods; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D010703:Phorbol Esters / Q000494:pharmacology; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D014162:Transfection / Q000379:methods
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008055:Lipids; D009687:Nuclear Proteins; D010703:Phorbol Esters; C091822:Prkcabp protein, mouse; D018091:Receptors, AMPA; D008239:Lysine; D000409:Alanine; C104722:glutamate receptor ionotropic, AMPA 2