Nature Neuroscience has a nice special focus on glia and disease. The featured reviews and perspective articles discuss multiple aspects of neuron-glia interactions and their role in disease. The reason why I am highlighting this collection here is that I have the feeling that this field could potentially be a nice playground for systems biology.
For example, Rossi and colleagues (2007) review the various metabolic processes affected during brain ischemia. Several of the examples discussed illustrate very well how the extent of brain damage is determined by the concurrent dynamics of both harmful and protective processes engaging complex interactions between neurons and astrocytes. A critical determinant for ischemic damage is the catastrophic loss of ATP levels caused by deficient glucose and oxygen delivery. Astrocytes have glycogen stores that can normally be converted to lactate which is exported to neurons to provide energy during phases of high activity. In absence of oxygen however, lactate can no longer be oxidized. In this case, glucose may then help delay loss of ATP levels, via anaerobic glycolysis. But this beneficial effect might be counteracted by lactic acidosis caused by continued glycolysis in the absence of O2, which is known to accentuate ischemic damage in the case of hyperglycemia. Moreover, acidosis may activate Na-H exchange, cytosolic Na accumulation, reversal of Na-Ca2+ exchange resulting in astrocyte Ca2+ overload, either impairing their protective functions or even killing them.
A similar complexity is seen in the events underlying ischemic glutamate release. Loss of cellular ATP levels impairs the function of the Na-K ATPase and thus disrupts ionic gradients. The resulting depolarization leads to a large increase in extracellular glutamate that is amplified by positive feedback, ultimately resulting in neuronal death by excitotoxicity. Astrocytes may contribute to increased extracellular glutamate levels via direct vesicular glutamate release and vesicular ATP release that in turn activates glutamate-permeable P2X receptors. Glutamate reuptake is normally carried out by five high-affinity sodium-dependent glutamate transporters. Disruption of transmembrane potential and of ionic gradients can cause transporter reversal thus further contributing to glutamate release. This depends in turn on the intracellular glutamate concentration which is much higher in astrocytes than neurons, determining the relative kinetic of neuronal and astrocytic reuptake/release as the ischemic perturbations progress. Further details are visible on Figure 3 from Rossi et al (2007):
Even if this short overview is condensed and incomplete, it suggests to me that quantitative measurements and integrated modeling could be quite helpful, if feasible, to understand the various contributions of the many processes involved and to identify potential points of protective synergies or characterize regimes under which the stability of the astrocyte-neuron system is catastrophically compromised. Perhaps this type of model and its calibration could even serve as a starting point to investigate the involvement of astrocytes in computational aspect of neuronal functions (Wang et al, 2006).