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The transition from early long-term potentiation (E-LTP) to late LTP (L-LTP)involves protein synthesis and degradation. L-LTP is blocked by inhibitingeither protein synthesis or proteasome-dependent degradation prior to andduring a tetanic stimulus, but paradoxically, L-LTP is not blocked whensynthesis and degradation are inhibited simultaneously, suggestingcounter-acting positive and negative proteins regulate L-LTP. To investigatethis paradox, we modeled LTP at the Schaffer collateral synapse. Ninedifferential equations describe the levels of positive and negative regulatorproteins (PP and NP) and transitions among five discrete synaptic states, abasal state (BAS), three E-LTP states (EP1, EP2, ED), and a L-LTP state (LP). Astimulus initiates the transition from BAS to EP1 and from EP1 to EP2,initiates the synthesis of PP and NP, and activates the ubiquitin-proteasomesystem (UPS). UPS mediates transitions of EP1 and EP2 to ED and the degradationof NP. The conversion of E-LTP to L-LTP is mediated by a PP-dependenttransition from ED to LP. NP mediates reversal of EP2 to BAS. This modelsimulates empirical observations: 1) normal L-LTP, 2) block by eitherproteasome inhibitor or protein synthesis inhibitor alone, and 3) preservationof L-LTP when both inhibitors are applied together. Elements of this abstractmodel can be correlated with specific molecules and processes. Moreover, themodel makes testable predictions, such as a unique synaptic state ED thatprecedes the transition to L-LTP, and a time window for the action of the UPS(during the transitions from EP1 and EP2 to ED). Tests of these predictionswill provide insights into the processes of long-term synaptic plasticity.

Paradoxical LTP maintenance with inhibition of protein synthesis and the  proteasome suggests a novel protein synthesis requirement for early LTP  reversal