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 3

Blocking GluA2-dependent AMPAR endocytosis promotes LTM formation.

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Blocking GluA2-dependent AMPAR endocytosis promotes LTM formation. (A) I...
(A) Inhibition of GluA2-dependent AMPAR endocytosis converts STM into LTM. wIA training produces only a STM that could be retrieved within 1 hour, but not at 24 hours, in control animals receiving bilateral intrahippocampal infusions of vehicle (n = 8 for either 1-hour or 24-hour test) immediately after training, however, this wIA training–induced STM is converted into a LTM that could be retrieved at 24 hours by bilateral intrahippocampal infusions of GluA23Y (n = 12) but not its control (n = 11). (B) Inhibition of GluA2-dependent AMPAR endocytosis does not affect LTM formation. Neither GluA23Y (n = 7) nor scr-GluA23Y (n = 7) applied via bilateral intrahippocampal infusions show any effect on LTM formation induced by sIA training compared with vehicle (n = 12). (C) sIA training specifically increases synaptic GluA2 and PKMζ. Sequential immunoblotting of synaptosomal fraction and total tissue lysates of hippocampal tissues collected from animals in A and B immediately after memory was tested at 24 hours. wIA and sIA training differentially affect the levels of GluA2 and PKMζ in the synaptic fraction but not in total lysates. Note wIA training does not affect PKMζ and only increases the synaptic GluA2 level in rats treated with GluA23Y, whereas sIA training increases the levels of both PKMζ and GluA2 in the synaptic fraction. Neither wIA nor sIA has any effect on GluA1. n = 5, *P < 0.05, **P < 0.01, Tukey’s post-hoc analysis.