Calcium Frequency Sets the Location of Calmodulin-Dependent Enzyme Activation in Dendritic Spines

Abstract

Specialized neuronal structures called dendritic spines are highly plastic, changing the connective strength of a synapse in response to electrical activity. During plasticity, calcium ions (Ca2+) flux into the spine, binding to the Ca2+-sensor calmodulin (CaM). Ca2+/CaM modulates downstream effector proteins including kinases, phosphatases, and ion channels, whose differential activation leads to either potentiation or depression of synaptic strength. CBP activation may depend on mechanisms such as feedback loops and spatial effects. We have shown that an additional mechanism, termed “competitive tuning”, occurs such that each CBP is maximally activated at different Ca2+ input signals. Tuning of competition among CBPs to bind Ca2+/CaM is sufficient to recreate in silico the observed in vivo Ca2+ frequency-dependence of several CBPs. However, the degree of competition among CBPs may be limited by their spatial distributions within the dendritic spine. Therefore, we present a detailed spatial-stochastic model of early signaling in synaptic plasticity and explore how competitive binding regulates the spatial and temporal activation of CBPs. Using the software MCell, a particle-based spatial-stochastic simulator, we monitor both concentrations and spatial locations of simulated Ca2+- CaM binding, Ca2+/CaM binding to nine explicitly-defined CBPs, and a set of CBP-initiated signaling pathways. Interestingly, we find that for a wide range of Ca2+ frequencies, competition among CBPs has little influence on the spatial locations of CBP activation. Instead, the locations of CBP activation seem to depend on diffusion, even over small distances in the 500nm-wide spine. Upon scaling the model diffusion parameters to account for molecular crowding, only high Ca2+ frequencies (∼100 Hz) evoke a location-dependence of CBP activation. Our results provide further mechanistic understanding into the regulation of synaptic plasticity and motivate future work to characterize how CBP activation depends on spatial effects.