UP consolidation: Substrates, explanatory power, and functional significance

Long-term potentiation (LTP) resembles memory in that it is initially unstable and then, over about 30 min, becomes increasingly resistant to disruption. Here we present an hypothesis to account for this initial consolidation effect and consider implications that follow from it. Anatomical studies indicate that UP is accompanied by changes in spine morphology and therefore likely involves cytoskeletal changes. Accordingly, theta bursts initiate calpain-mediated proteolysis of the actin cross-linking protein spectrin and trigger actin polymerization in spine heads, two effects indicative of cytoskeletal reorganization. Polymerization occurs within 2 min, has the same threshold as UP, is dependent on integrins, and becomes resistant to disruption over 30 min. We propose that the stabilization of the new cytoskeletal organization, and thus of a new spine morphology, underlies the initial phase of UP consolidation. This hypothesis helps explain the diverse array of proteins and signaling cascades implicated in UP, as well as the often-contradictory results about contributions of particular molecules. It also provides a novel explanation for why UP is potently modulated by factors likely to be released during theta trains (e.g., BDNF). Finally, building on evidence that normal patterns of activity reverse UP, we suggest that consolidation provides a delay that allows brain networks to sculpt newly formed memories. (c) 2006 Elsevier Ltd. All rights reserved.