title: Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis.
abstract: Long-term potentiation (LTP) of synaptic strength between hippocampal neurons is associated with learning and memory, and LTP dysfunction is thought to underlie memory loss. LTP can be temporally and mechanistically classified into decaying (early-phase) LTP and nondecaying (late-phase) LTP. While the nondecaying nature of LTP is thought to depend on protein synthesis and contribute to memory maintenance, little is known about the mechanisms and roles of decaying LTP. Here, we demonstrated that inhibiting endocytosis of postsynaptic α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs) prevents LTP decay, thereby converting it into nondecaying LTP. Conversely, restoration of AMPAR endocytosis by inhibiting protein kinase Mζ (PKMζ) converted nondecaying LTP into decaying LTP. Similarly, inhibition of AMPAR endocytosis prolonged memory retention in normal animals and reduced memory loss in a murine model of Alzheimer's disease. These results strongly suggest that an active process that involves AMPAR endocytosis mediates the decay of LTP and that inhibition of this process can prolong the longevity of LTP as well as memory under both physiological and pathological conditions.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Dong
authors.forename: Huili
authors.initials: H
authors.lastname: Han
authors.forename: Hongjie
authors.initials: H
authors.lastname: Li
authors.forename: Yanrui
authors.initials: Y
authors.lastname: Bai
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Man
authors.initials: M
authors.lastname: Tu
authors.forename: Yan
authors.initials: Y
authors.lastname: Peng
authors.forename: Limin
authors.initials: L
authors.lastname: Zhou
authors.forename: Wenting
authors.initials: W
authors.lastname: He
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Wu
authors.forename: Tao
authors.initials: T
authors.lastname: Tan
authors.forename: Mingjing
authors.initials: M
authors.lastname: Liu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.forename: Weihui
authors.initials: W
authors.lastname: Zhou
authors.forename: Wuyang
authors.initials: W
authors.lastname: Jin
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.forename: Todd Charlton
authors.initials: TC
authors.lastname: Sacktor
authors.forename: Tingyu
authors.initials: T
authors.lastname: Li
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000503:physiopathology; D004705:Endocytosis; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D008569:Memory Disorders / Q000378:metabolism*; D057567:Memory, Long-Term; D008570:Memory, Short-Term; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D011493:Protein Kinase C; D018091:Receptors, AMPA; D000099221:Protein Kinase C zeta; C104722:glutamate receptor ionotropic, AMPA 2