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Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis
Zhifang Dong, … , Weihong Song, Yu Tian Wang
Zhifang Dong, … , Weihong Song, Yu Tian Wang
Published December 1, 2014
Citation Information: J Clin Invest. 2015;125(1):234-247. https://doi.org/10.1172/JCI77888.
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Research Article Neuroscience

Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis

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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

Zhifang Dong, Huili Han, Hongjie Li, Yanrui Bai, Wei Wang, Man Tu, Yan Peng, Limin Zhou, Wenting He, Xiaobin Wu, Tao Tan, Mingjing Liu, Xiaoyan Wu, Weihui Zhou, Wuyang Jin, Shu Zhang, Todd Charlton Sacktor, Tingyu Li, Weihong Song, Yu Tian Wang

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Figure 2

Inhibition of AMPAR endocytosis rescues PKMζ knockdown–induced impairment of nondecaying LTP in freely moving rats.

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Inhibition of AMPAR endocytosis rescues PKMζ knockdown–induced impairmen...
(A) Diagram illustrating the experimental protocols for the electrophysiological recordings in animals receiving bilateral intrahippocampal infusions of lentiviral (LV) shRNA (1.5 μl/hippocampus) and i.c.v. infusion of GluA23Y or scr-GluA23Y peptide (500 pmol). (B) Representative images and immunoblots illustrating the injection site and efficiency of lentiviral shRNA-mediated PKMζ knockdown. PKMζ shRNA selectively reduced the level of PKMζ but not PKCλ/ι expression. Scale bar: 2 mm (left); 50 μm (right). n = 5, *P < 0.05, Student’s t test. (C) shRNA-mediated knockdown of PKMζ causes decay of sHFS-induced nondecaying LTP via GluA2-AMPAR endocytosis-dependent mechanism. The plot and bar graph show that lentiviral shRNA knockdown of PKMζ (LVPKMζ shRNA+scr-GluA23Y; n = 3) causes sHFS-induced nondecaying LTP to decay and this is prevented by application of GluA23Y (LVPKMζ shRNA+GluA23Y; n = 5) immediately after sHFS delivery. The control viral GFP has no observable effect in the presence of either GluA23Y (LVEGFP+ GluA23Y; n = 5) or its control (LVEGFP+scr-GluA23Y; n = 3). **P < 0.01, Tukey’s post-hoc analysis.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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