Abstract
Calmodulin-dependent kinase II (CaMKII) has long been known to play an important role in learning and memory as well as long term potentiation (LTP). More recently it has been suggested that it might be involved in the time averaging of synaptic signals, which can then lead to the high precision of information stored at a single synapse. However, the role of the scaffolding molecule, neurogranin (Ng), in governing the dynamics of CaMKII is not yet fully understood. In this work, we adopt a rule-based modeling approach through the Monte Carlo method to study the effect of Ca2+ signals on the dynamics of CaMKII phosphorylation in the postsynaptic density (PSD). Calcium surges are observed in synaptic spines during an EPSP and back-propagating action potential due to the opening of NMDA receptors and voltage dependent calcium channels. Using agent-based models, we computationally investigate the dynamics of phosphorylation of CaMKII monomers and dodecameric holoenzymes. The scaffolding molecule, Ng, when present in significant concentration, limits the availability of free calmodulin (CaM), the protein which activates CaMKII in the presence of calcium. We show that Ng plays an important modulatory role in CaMKII phosphorylation following a surge of high calcium concentration. We find a non-intuitive dependence of this effect on CaM concentration that results from the different affinities of CaM for CaMKII depending on the number of calcium ions bound to the former. It has been shown previously that in the absence of phosphatase, CaMKII monomers integrate over Ca2+ signals of certain frequencies through autophosphorylation (Pepke et al, Plos Comp. Bio., 2010). We also study the effect of multiple calcium spikes on CaMKII holoenzyme autophosphorylation, and show that in the presence of phosphatase, CaMKII behaves as a leaky integrator of calcium signals, a result that has been recently observed in vivo. Our models predict that the parameters of this leaky integrator are finely tuned through the interactions of Ng, CaM, CaMKII, and PP1, providing a mechanism to precisely control the sensitivity of synapses to calcium signals. Author Summary not valid for PLOS ONE submissions.
Highlights
Information is stored in the brain through synaptic plasticity
We study the effect of multiple calcium spikes on calmodulin-dependent protein kinase II (CaMKII) holoenzyme autophosphorylation, and show that in the presence of phosphatase, CaMKII behaves as a leaky integrator of calcium signals, a result that has been recently observed in vivo
We create a computational model of a calcium signaling pathway that sets off a chain reaction in CaMKII phosphorylation, eventually leading to synaptic plasticity
Summary
It has been reported that synaptic strength is highly correlated with the size of the spine head, and the precision of information stored at a single synapse is quite high despite the stochastic variability of synaptic activation [1,2,3]. Structural changes to the postsynaptic spine that can lead to spine enlargement, and structural plasticity are triggered by Ca2+ signaling [4, 5] Time averaging of these calcium signals has been suggested as a plausible mechanism for achieving the high precision of information processing observed in spines. CaMKII is an autophosphorylating kinase [6, 7] [8,9,10]; in postsynaptic densities (PSD), CaMKII has been shown to play an important role in learning and memory [11]. Activation of CaMKII is exquisitely regulated at multiple levels as summarized below
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