Diffusion modeling of ATP signaling suggests a partially regenerative mechanism underlies astrocyte intercellular calcium waves

Abstract

Network signaling through astrocyte syncytiums putatively contribute to the regulation of a number of both physiological and pathophysiological processes in the mammalian central nervous system. As such, an understanding of the underlying mechanisms is critical to determining any roles played by signaling through astrocyte networks. Astrocyte signaling is primarily mediated by the propagation of intercellular calcium waves (ICW) in the sense that paracrine signaling results in measurable intracellular calcium transients. Although the molecular mechanisms are relatively well known, there is confli cting data regarding the mechanism by which the signal propagates through the network. Experimentally there is evidence for both a point source signaling model in which adenosine triphosphate (ATP) is released by an initially activated astrocyte only, and a regenerative signaling model in which downstream astrocytes release ATP. We modeled both conditions as a simple lumped parameter phenomenological diffusion model and show that the only possible mechanism that can accurately reproduce experimentally measured results is a dual signaling mechanism that incorporates elements of both proposed signaling models. Specific ally, we were able to accurately simulate experimentally measured in vitro ICW dynamics by assuming a point source signaling model with a downstream regenerative component. These results suggest that seemingly confli cting data in the literature are actually complimentary, and represents a highly effic ient and robustly engineered signaling mechanism. © 2008 MacDonald, Yu, Buibas and Silva.