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

Abstract: The transition from early long-term potentiation (E-LTP) to late LTP (L-LTP) involves protein synthesis and degradation. L-LTP is blocked by inhibiting either protein synthesis or proteasome-dependent degradation prior to and during a tetanic stimulus, but paradoxically, L-LTP is not blocked when synthesis and degradation are inhibited simultaneously, suggesting counter-acting positive and negative proteins regulate L-LTP. To investigate this paradox, we modeled LTP at the Schaffer collateral synapse. Nine differential equations describe the levels of positive and negative regulator proteins (PP and NP) and transitions among five discrete synaptic states, a basal state (BAS), three E-LTP states (EP1, EP2, ED), and a L-LTP state (LP). A stimulus initiates the transition from BAS to EP1 and from EP1 to EP2, initiates the synthesis of PP and NP, and activates the ubiquitin-proteasome system (UPS). UPS mediates transitions of EP1 and EP2 to ED and the degradation of NP. The conversion of E-LTP to L-LTP is mediated by a PP-dependent transition from ED to LP. NP mediates reversal of EP2 to BAS. This model simulates empirical observations: 1) normal L-LTP, 2) block by either proteasome inhibitor or protein synthesis inhibitor alone, and 3) preservation of L-LTP when both inhibitors are applied together. Elements of this abstract model can be correlated with specific molecules and processes. Moreover, the model makes testable predictions, such as a unique synaptic state ED that precedes 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 predictions will provide insights into the processes of long-term synaptic plasticity.