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1091-6490117402020Oct06Proceedings of the National Academy of Sciences of the United States of AmericaProc Natl Acad Sci U S AGRIP1 regulates synaptic plasticity and learning and memory.250852509125085-2509110.1073/pnas.2014827117Hebbian plasticity is a key mechanism for higher brain functions, such as learning and memory. This form of synaptic plasticity primarily involves the regulation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) abundance and properties, whereby AMPARs are inserted into synapses during long-term potentiation (LTP) or removed during long-term depression (LTD). The molecular mechanisms underlying AMPAR trafficking remain elusive, however. Here we show that glutamate receptor interacting protein 1 (GRIP1), an AMPAR-binding protein shown to regulate the trafficking and synaptic targeting of AMPARs, is required for LTP and learning and memory. GRIP1 is recruited into synapses during LTP, and deletion of Grip1 in neurons blocks synaptic AMPAR accumulation induced by glycine-mediated depolarization. In addition, Grip1 knockout mice exhibit impaired hippocampal LTP, as well as deficits in learning and memory. Mechanistically, we find that phosphorylation of serine-880 of the GluA2 AMPAR subunit (GluA2-S880) is decreased while phosphorylation of tyrosine-876 on GluA2 (GluA2-Y876) is elevated during chemically induced LTP. This enhances the strength of the GRIP1-AMPAR association and, subsequently, the insertion of AMPARs into the postsynaptic membrane. Together, these results demonstrate an essential role of GRIP1 in regulating AMPAR trafficking during synaptic plasticity and learning and memory.TanHan LHL0000-0001-5163-7720Solomon H. Snyder Department of Neuroscience and Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.ChiuShu-LingSL0000-0003-4429-7830Solomon H. Snyder Department of Neuroscience and Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.Institute of Cellular and Organismic Biology, Academia Sinica, 11529 Taipei, Taiwan.ZhuQianwenQ0000-0003-2799-2372Solomon H. Snyder Department of Neuroscience and Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.HuganirRichard LRL0000-0001-9783-5183Solomon H. Snyder Department of Neuroscience and Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205; rhuganir@jhmi.edu.engR01 MH112808MHNIMH NIH HHSUnited StatesR01 NS036715NSNINDS NIH HHSUnited StatesR37 NS036715NSNINDS NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., Extramural20200918
United StatesProc Natl Acad Sci U S A75058760027-84240Adaptor Proteins, Signal Transducing0Carrier Proteins0Grip1 protein, mouse0Nerve Tissue Proteins0Receptors, AMPA0Receptors, Glutamate0alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor, humanP6W5IXV8V9glutamate receptor ionotropic, AMPA 2IMAdaptor Proteins, Signal TransducinggeneticsAnimalsCarrier ProteinsgeneticsGene Expression RegulationgeneticsHippocampusmetabolismHumansLearningphysiologyMemoryphysiologyMiceMice, KnockoutNerve Tissue ProteinsgeneticsNeuronal PlasticitygeneticsNeuronsmetabolismPhosphorylationgeneticsReceptors, AMPAgeneticsReceptors, GlutamategeneticsSynapsesgeneticsmetabolismAMPA receptorGRIP1LTPlearning and memorysynaptic plasticityThe authors declare no competing interest.202092060202011256020209195292021318ppublish32948689PMC754724410.1073/pnas.20148271172014827117Volk L., Chiu S. L., Sharma K., Huganir R. L., Glutamate synapses in human cognitive disorders. Annu. Rev. 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