The sensitivity of memory consolidation and reconsolidation to inhibitors of protein synthesis and kinases: Computational analysis

Memory consolidation and reconsolidation require kinase activation and protein synthesis. Blocking either process during or shortly after training or recall disrupts memory stabilization, which suggests the existence of a critical time window during which these processes are necessary. Using a computational model of kinase synthesis and activation, we investigated the ways in which the dynamics of molecular positive-feedback loops may contribute to the time window for memory stabilization and memory maintenance. In the models, training triggered a transition in the amount of kinase between two stable states, which represented consolidation. Simulating protein synthesis inhibition (PSI) from before to 40 min after training blocked or delayed consolidation. Beyond 40 min, substantial (>95%) PSI had little effect despite the fact that the elevated amount of kinase was maintained by increased protein synthesis. However, PSI made established memories labile to perturbations. Simulations of kinase inhibition produced similar results. In addition, similar properties were found in several other models that also included positive-feedback loops. Even though our models are based on simplifications of the actual mechanisms of molecular consolidation, they illustrate the practical difficulty of empirically measuring "time windows" for consolidation. This is particularly true when consolidation and reconsolidation of memory depends, in part, on the dynamics of molecular positive-feedback loops.