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

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 6

GluA2-dependent AMPAR endocytosis contributes to memory impairment in AD mice.

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GluA2-dependent AMPAR endocytosis contributes to memory impairment in AD...
(A) Inhibition of AMPAR endocytosis prevents the impairment of LTP maintenance in AD mice. The plot of fEPSP slope shows that sHFS is capable of inducing nondecaying LTP in mice receiving GluA23Y but not control peptide. n = 4 in each group; *P < 0.05, Student’s t test. (B) Inhibition of AMPAR endocytosis reduces impairment of memory maintenance in AD mice. IA tests show that LTM gradually decayed between 15 and 30 days and this memory impairment is fully rescued by chronic application of GluA23Y (n = 20) but not its control (n = 18). **P < 0.01, Tukey’s post-hoc analysis. (C and D) Inhibition of AMPAR endocytosis improves spatial learning and memory in water maze tests. Mice treated with GluA23Y (n = 7) (C) spent less time finding the hidden platform on training day 4 and 5 and (D) spent much more time in the platform-located quadrant during probe testing compared with mice receiving scr-GluA2 (n = 6). Dashed line indicates the time in the platform-located quadrant by chance during probe testing. *P < 0.05, Tukey’s post-hoc analysis. (E) The increase in synaptic GluA2 is critical for the improved memory maintenance in AD mice. GluA23Y, but not scr-GluA23Y, rescues the sIA training–induced increase in synaptic GluA2, without affecting the deficit in sIA training–induced synaptic localization of PKMζ. n = 5; *P < 0.05, Student’s t test. (F) Chronic application of GluA23Y, but not scr-GluA2Y, decreases neuritic plaque formation (arrows). Scale bar: 500 μm. n = 12 in each group; *P < 0.05, Student’s t test.