A quantitative model of ATP-mediated calcium wave propagation in astrocyte networks

Abstract

In the past attention has mainly been focused on neurons and the role they play, both individually and as parts of networks, in the functioning of the brain and nervous system. However, glial cells outnumber neurons in the brain, and it is now becoming apparent that, far from just performing supportive and housekeeping tasks, they are also actively engaged in information processing and possibly even learning. Communication in glial cells is manifested by waves of calcium ions (Ca2+) that are released from internal stores, and these waves are observed experimentally using fluorescent markers attached to the ions. The waves can be initiated by stimulation of a single cell, and initially it was assumed that the transmission mechanism involved the passage of an intercellular signalling agent passing through gap junctions connecting the cells. However, a surprising feature is that in many cases the calcium waves can cross cell-free zones, thus indicating the presence of an extracellular messenger. We have constructed a mathematical model of calcium wave propagation in networks of model astrocytes, these being a subclass of glial cells. The extracellular signalling agent is ATP (adenosine triphosphate) and it acts on metabotropic purinergic receptors on the astrocytes, initiating a G-protein cascade leading to the production of inositol trisphosphate (IP3) and the subsequent release of Ca2+ from intracellular stores via IP3-sensitive channels. Stimulation of one cell (by a pulse of ATP or by raising the IP3 level) leads to the regenerative release of ATP both from this cell and from neighbouring cells, and hence a Ca2+ wave. Results are given for the propagation of Ca2+ waves in two-dimensional arrays of model astrocytes and also in lanes with cell-free zones in between. These theoretical considerations support the concept of extracellular purinergic transmission in astrocyte networks.