The trinity of Ca2+ sources for the exocytotic glutamate release from astrocytes

A developing body of evidence implicates astrocytes as active participants in multi-directional signaling in the central nervous system (CNS) [reviewed in (Haydon and Carmignoto, 2006; Theodosis et al., 2008)]. Astrocytes communicate with neurons (Nedergaard, 1994; Parpura et al., 1994), endothelial cells of the cerebrovasculature (Zonta et al., 2003; Mulligan and MacVicar, 2004), and microglia (Davalos et al., 2005). They appear to be an integral part of neural communication throughout the CNS. For example, in the hippocampus, astrocytes integrate neuronal signals (Perea and Araque, 2005), potentiate transmitter release at single synapses (Perea and Araque, 2007), enhance long-term potentiation (Pascual et al., 2005), and synchronize neuronal activity (Fellin et al., 2004). In the thalamus, astrocytes have been shown to drive neuronal activity as a consequence of astrocytic intrinsic Ca2+ oscillations (Parri et al., 2001). In the supraoptic nucleus of the hypothalamus, morphological plasticity of astrocytes (Hatton, 2004) leading to differential synaptic coverage by astrocytic processes can modulate the activity of the output neurons (Panatier et al., 2006). The abundance of astrocytes and their proximity to neurons enables their communication with neurons. Early studies indicated the numerical preponderance of glial cells in the CNS. For example, in layers I and IV of the rat cerebral cortex, glial cells consisting of astrocytes and oligodendrocytes, outnumbered neurons 3 to 1 (Bass et al., 1971). As more sophisticated tools for cell counting emerged, it appears, however, that the glia to neuron ratio in human cortex is ~ 1.65:1, while in rodent this ratio is about 0.3:1 (Nedergaard et al., 2003; Sherwood et al., 2006). Astrocytes occupy distinct domains within the CNS, only at the cells’ peripheries do their processes overlap (Bushong et al., 2002; Ogata and Kosaka, 2002). Within their individual domains astrocytes have extensive morphological interactions with neurons. For example, in the cortex of adult mice, one astrocyte may contact 4 to 8 neurons and surround ~300 to 600 neuronal dendrites (Halassa et al., 2007). In the hippocampus, astrocytes are positioned to contact even more synapses. In adult rats, one astrocyte is estimated to contact ~140,000 synapses of CA1 pyramidal cells (Bushong et al., 2002). Classically, the intimate position of astrocytic processes around the neurons and the synapses has been solely attributed to glutamate uptake and regulation of extracellular K+ by astrocytes. To provide these services, astrocytes possess excitatory amino acid transporters (EAAT’s) (Huang and Bergles, 2004; Tzingounis and Wadiche, 2007; Yang and Rothstein, 2009) and K+ inward rectifying (Kir) channels (Sontheimer et al., 1994; Kofuji and Newman, 2009), respectively. However, it is also at synapses where astrocytes have been shown to have modulatory effects on the activities of presynaptic and postsynaptic neurons by astrocytic ability to release a variety of transmitters using many different mechanisms [reviewed in (Malarkey and Parpura, 2009)]. This led to the concept of a functional tripartite synapse (Araque et al., 1999), a topic that has been recently reviewed elsewhere (Ni et al., 2007; Halassa and Haydon, 2009). In this review we focus on the Ca2+ sources for the exocytotic release of the excitatory transmitter glutamate from astrocytes, which can readily occur under physiological conditions (Parpura and Haydon, 2000). We start with a historical brief on the Ca2+-dependent glutamate release from astrocytes [reviewed in detail in (Montana et al., 2004)]. We then discuss the trinity of Ca2+ sources for this release: intracellular stores, extracellular space and mitochondria. An understanding of how these Ca2+ sources contribute to the glutamate release will provide information on glial functions in heath and disease and may also introduce opportunities for medical intervention.