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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.
Introduction
Activity-dependent long-term potentiation (LTP) of synaptic efficacy at the glutamatergic synapses in the hippocampus is the most well-characterized form of synaptic plasticity and has long been considered as a cellular mechanism underlying learning and memory (1-4). In support of the putative role of LTP in learning and memory, extensive work in in vivo animals has revealed a strong correlation between the maintenance of LTP and the maintenance of memory (5-7). Therefore, understanding the processes underlying LTP maintenance may in turn provide important information about the mechanisms of memory storage. LTP maintenance is often temporally and mechanistically divided into 2 phases, the decaying (or early) phase of LTP and the nondecaying (or late) phase of LTP (8, 9). Decaying LTP is often induced experimentally in brain slices and in vivo animals with a weak induction protocol (such as a single tetanic burst), can decay within hours, and does not depend on the synthesis of new protein(s). Conversely, nondecaying LTP can be induced with strong stimulation protocols (such as multiple tetani in quick succession), lasts hours and days, and may require new protein synthesis (10-13). Decaying LTP may be converted into nondecaying LTP, and such a conversion is thought to be a critical process for the conversion of...