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Calcium waves represent a widespread form of intercellular communication. Although they have been thought for a long time to require gap junctions, we recently demonstrated that mouse cortical astrocytes use an extracellular messenger for calcium wave propagation. The present experiments identify ATP as a major extracellular messenger in this system. Medium collected from astrocyte cultures during (but not before) calcium wave stimulation contains ATP. The excitatory effects of medium samples and of ATP are blocked by purinergic receptor antagonists and by pretreatment with apyrase; these same purinergic receptor antagonists block propagation of electrically evoked calcium waves. ATP, applied at the concentration measured in medium samples, evokes responses that are qualitatively and quantitatively similar to those evoked by those medium samples. These data implicate ATP as an important transmitter between CNS astrocytes.Key words: glia; astrocytes; calcium waves; ATP; extracellular signal; suramin; apyrase; purinergic; electrical stimulation Intercellular calcium waves, i.e., rises in intracellular free calcium that propagate between neighboring cells, occur widely among different cell types throughout the animal kingdom (Cornell-Bell et al., 1990;Boitano et al., 1992;Enomoto et al., 1992;Demer et al., 1993;Nathanson et al., 1995;C ao et al., 1997;Young et al., 1996;Jørgensen et al., 1997;Newman and Z ahs, 1997). Although we are at an early stage of understanding the f unction of such waves, one must consider that glial calcium waves may provide an information-processing system operating in parallel with neuronal circuits within the nervous system. There is clear evidence of interaction between glial calcium waves and neurons; neuronal activity can directly evoke glial calcium waves (Dani et al., 1992), and glial calcium waves can directly evoke calcium transients and electrical activity in neurons (Nedergaard, 1994;Parpura et al., 1994;Hassinger et al., 1995;Newman and Z ahs, 1998). Understanding how glial calcium waves could contribute to information processing requires an understanding of the mechanisms underlying calcium wave propagation.For some years, glial calcium waves have been thought to propagate through gap junctions (Boitano et al., 1992;Charles et al., 1993;Sanderson et al., 1994;Sneyd et al., 1994Sneyd et al., , 1995. We demonstrated recently that an extracellular communication system can provide a dominant path for glial calcium wave propagation (Hassinger et al., 1996), because calcium waves can propagate between physically separated astrocytes, and the extent and direction of calcium wave propagation are significantly influenced by movement of the extracellular medium. T wo subsequent publications now confirm that astrocytes do not absolutely require functional gap junction coupling for calcium wave propagation (Guan et al., 1997;Naus et al., 1997). Taken together, the newer literature supports the idea that substance(s) released from astrocytes can activate receptor systems on adjacent astroc...

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Cortical spreading depression (CSD), a slowly propagated wave of depolarization followed by suppression of brain activity, is a remarkably complex event that involves dramatic changes in neural and vascular function. Since its original description in the 1940s, CSD has been hypothesized to be the underlying mechanism of the migraine aura. Substantial evidence from animal models provides indirect support for this hypothesis, and studies showing that CSD is common in humans with brain injury clearly demonstrate that the phenomenon can occur in the human brain. Considerable uncertainty about the role of CSD in migraine remains, however, and key questions about how this event is initiated, how it spreads, and how it might cause migraine symptoms remain unanswered. This Review summarizes current concepts of CSD and its potential roles in migraine, and addresses ongoing studies aimed at a clearer understanding of this fundamental brain phenomenon.