Geometric control of frequency modulation of cAMP oscillations due to Ca²⁺-bursts in dendritic spines

Abstract

The spatiotemporal regulation of cAMP and its dynamic interactions with other second messengers such as calcium are critical features of signaling specificity required for neuronal development and connectivity. cAMP is known to contribute to long-term potentiation and memory formation by controlling the formation and regulation of dendritic spines. Despite the recent advances in biosensing techniques for monitoring spatiotemporal cAMP dynamics, the underlying molecular mechanisms that attribute to the subcellular modulation of cAMP remain unknown. In the present work, we model the spatio-temporal dynamics of calciuminduced cAMP signaling pathway in dendritic spines. Using a 3D reaction-diffusion model, we investigate the effect of different spatial characteristics of cAMP dynamics that may be responsible for subcellular regulation of cAMP concentrations. Our model predicts that the volume-to-surface ratio of the spine, regulated through the spine head size, spine neck size, and the presence of physical barriers (spine apparatus) is an important regulator of cAMP dynamics. Furthermore, localization of the enzymes responsible for the synthesis and degradation of cAMP in different compartments also modulates the oscillatory patterns of cAMP through exponential relationships. Our findings shed light on the significance of complex geometric and localization relationships for cAMP dynamics in dendritic spines.

Computational modeling reveals frequency modulation of calcium-cAMP/PKA pathway in dendritic spines

“…These enzymes can also be localized by A-kinase anchoring proteins (AKAPs) and change cAMP/PKA dynamics further [83][84][85]. The effect of spine size and enzyme localizations are considered in a companion study [23]. Figure 7: The frequency control in the modeled cAMP/PKA pathway from calcium stimulation through PKA.…”

“…All the biochemical species including the membranebound ones are well-mixed across this compartment. A separate spatial model is presented in [23].…”

GAMer 2: A System for 3D Mesh Processing of Cellular Electron Micrographs

“…For example, fluorescence experiments have shown that the dendritic spine necks act as a diffusion barrier to calcium ions, preventing ions from entering the dendritic shaft [59]. Complementary to this and other experiments, various physical models solving reaction-diffusion equations in idealized geometries have been developed to further interrogate the structure-function relationships [41,53,[64][65][66][67].…”

Computational Modeling Reveals Frequency Modulation of Calcium-cAMP/PKA Pathway in Dendritic Spines

“…All the biochemical species, including the membrane-bound ones, are well-mixed across this compartment. A separate spatial model is presented in (62).…”