How can memories last for days, years, or a lifetime? Proposed mechanisms for maintaining synaptic potentiation and memory.

With memory encoding reliant on persistent changes in the properties of synapses, a key question is how can memories be maintained from days to months or a lifetime given molecular turnover? It is likely that positive feedback loops are necessary to persistently maintain the strength of synapses that participate in encoding. Such feedback may occur within signal-transduction cascades and/or the regulation of translation, and it may occur within specific subcellular compartments or within neuronal networks. Not surprisingly, numerous positive feedback loops have been proposed. Some posited loops operate at the level of biochemical signal-transduction cascades, such as persistent activation of Ca/calmodulin kinase II (CaMKII) or protein kinase Mζ. Another level consists of feedback loops involving transcriptional, epigenetic and translational pathways, and autocrine actions of growth factors such as BDNF. Finally, at the neuronal network level, recurrent reactivation of cell assemblies encoding memories is likely to be essential for late maintenance of memory. These levels are not isolated, but linked by shared components of feedback loops. Here, we review characteristics of some commonly discussed feedback loops proposed to underlie the maintenance of memory and long-term synaptic plasticity, assess evidence for and against their necessity, and suggest experiments that could further delineate the dynamics of these feedback loops. We also discuss crosstalk between proposed loops, and ways in which such interaction can facilitate the rapidity and robustness of memory formation and storage.