Calcium Waves in Astrocyte Networks: Theory and Experiments

In the central nervous system (CNS), astrocytes participate in supportive functions, such as metabolism, ion homeostasis, neurotransmitter recycling and tissue integrity-restoration. However, astrocytes are also deeply involved in a variety of complex phenomena, including CNS physiology, information processing, and synaptic plasticity (Fellin, 2009). These make the investigation of astrocytes (dis)functions as challenging as of neurons and synapses.

Interestingly, astrocytes are excitable cells like neurons. They base their communication on spontaneous or evoked cytosolic Ca²⁺ variations, instead of membrane electrical transients. Their remarkable morphology supports intercellular signaling as they form interconnected networks of cells coupled by gap-junctions, where each unit occupies a virtually non-overlapping domain of the inter-neuronal space. Surprisingly, astrocytes communicate also to neurons and synapses. In fact, they extend membrane processes to simultaneously contact hundreds of neuronal dendrites, thousands of synapses and even blood vessels. Indeed, astrocytes control the vasculature tone and they are likely to sense neuronal energy-demand and gate its consumption. Their physiology is thus bidirectionally linked to neuronal and synaptic activity, as they are capable of selectively respond to it on a millisecond time scale, by releasing specific neuroactive molecules (Ni et al., 2007). Notable are the discoveries of the interaction with synaptic physiology and plasticity that led to revisiting information transfer between neurons, with the proposed concept of a “tri-partite synapse” (Perea and Araque, 2002).

In this issue, MacDonald et al. (2008) focus on the astrocyte-to-astrocyte communication, by exploring the long-range propagation mechanisms of intracellular calcium waves (ICW). These represent a form of intercellular signaling in astrocyte networks, where ATP release is initiated by the intracellular Ca²⁺ elevation, and whose diffusion acts as cell-to-cell transmitter. Authors employ in vitro calcium imaging in astrocytes cultures and a simple phenomenological mathematical model. Through such a combined approach, they examine two apparently conflicting scenarios, as debated in the literature: during ICW, (1) ATP is secreted by one cell (i.e., a point-source) and diffuses activating nearby astrocytes, or (2) ATP-induced cell activation is actively regenerated by downstream astrocytes, which in turn secrete ATP, similarly to propagation of an action-potential through a myelinated axon.

Only through a combination of (1) and (2), resulting in both regenerative and diffusive mechanisms, the model is able to match quantitatively the in vitro ICW. This result reconciles elegantly the previous debate between single-point source models and fully regenerative signaling models, and it is particularly significant due to the extremely simple nature of the model. Even though several biophysical details underlying ATP diffusion and single-cell “excitability” were neglected, this model allows for systematic interpretation and analysis of the relationship between single-cell and network emerging properties, which is hard to obtain in accurate biophysical descriptions.

It is intriguing to outline the similarity between the astrocyte model introduced here, and the spiking network models of the integrate-and-fire family. The last are reduced models of neuronal excitability, shown to capture quantitatively the experimental responses from cells in large networks (Jolivet et al., 2008). Similarly, MacDonald et al. (2008) identifies a minimal description to predict network-level ICW propagation. These considerations therefore suggest that the two modeling approaches may be unified, incorporating spiking neurons, chemical synapses as well as astrocytes, ICW and ATP-diffusion. The results of such attempts might be valuable to identify global activity regimes, to be explored in greater details through large-scale simulations (Markram, 2006) that incorporate anatomically precise details on neurons, astrocytes and the intercellular environment (Helmstaedter et al., 2009).