Subunit exchange enhances information retention by CaMKII in dendritic spines

Abstract

Molecular bistables are strong candidates for long-term information storage, for example, in synaptic plasticity. CaMKII is a highly expressed synaptic protein which has been proposed to form a molecular bistable switch capable of maintaining its state for years despite protein turnover and stochastic noise. It has recently been shown that CaMKII holoenzymes exchange subunits among themselves. Here we used computational methods to analyze the effect of subunit exchange on the CaMKII pathway in the presence of diffusion in two different microenvironments, the Post Synaptic Density (PSD) and spine cytosol. We show that in the PSD, subunit exchange leads to coordinated switching and prolongs state stability of the fraction of CaMKII that is present in clusters; and underlies spreading of activation among the remaining CaMKII that is uniformly distributed. Subunit exchange increases the robustness of the CaMKII switch measured as range of bistability both with respect to protein phosphatase 1 (PP1) levels and protein turnover rates. In the phosphatase-rich spine cytosol, subunit exchange leads to slower decay of activity following calcium stimuli. We find that subunit exchange can explain two time-courses of CaMKII activity decay observed in recent experiments monitoring endogenous activity of CaMKII in the spine. Overall, CaMKII exhibits multiple timescales of activity in the synapse and subunit exchange enhances the information retention ability of CaMKII by improving the stability of its switching in the PSD, and by slowing the decay of its activity in the spine cytosol. The existence of diverse timescales in the synapse has important theoretical implications for memory storage in networks.\n\nSignificance StatementDespite everyday forgetfulness, we can recall some memories years after they were formed. How are we able to protect some memories for so long? Previous work has shown that the abundant brain protein Calcium/calmodulin dependent protein Kinase II (CaMKII) can form a very stable binary switch which can store information for years. Building on this work, we analyzed the implications of a recently discovered phenomenon of subunit exchange on the state switching properties of CaMKII. In subunit exchange fragments of one CaMKII molecule detatch and exchange with another. We discovered that this improves the information retention ability of CaMKII both in the context where it stores information for long times, and also where it integrates information over the timescale of minutes.