Coupled feedback loops maintain synaptic long-term potentiation: A computational model of PKMzeta synthesis and AMPA receptor trafficking

In long-term potentiation (LTP), one of the most studied types of neural plasticity, synaptic strength is persistently increased in response to stimulation. Although a number of different proteins have been implicated in the sub-cellular molecular processes underlying induction and maintenance of LTP, the precise mechanisms remain unknown. A particular challenge is to demonstrate that a proposed molecular mechanism can provide the level of stability needed to maintain memories for months or longer, in spite of the fact that many of the participating molecules have much shorter life spans. Here we present a computational model that combines simulations of several biochemical reactions that have been suggested in the LTP literature and show that the resulting system does exhibit the required stability. At the core of the model are two interlinked feedback loops of molecular reactions, one involving the atypical protein kinase PKMζ and its messenger RNA, the other involving PKMζ and GluA2-containing AMPA receptors. We demonstrate that robust bistability-stable equilibria both in the synapse's potentiated and unpotentiated states-can arise from a set of simple molecular reactions. The model is able to account for a wide range of empirical results, including induction and maintenance of late-phase LTP, cellular memory reconsolidation and the effects of different pharmaceutical interventions.