Geometric Control of Frequency Modulation of cAMP Oscillations due to Calcium in Dendritic Spines

The spatiotemporal regulation of cyclic adenosine monophosphate (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 this work, we model the spatiotemporal dynamics of calcium-induced cAMP signaling pathway in dendritic spines. Using a three-dimensional 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/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.