Neurone-to-astrocyte signalling in the brain represents a distinct multifunctional unit

Astrocytes can respond to neurotransmitters released at the synapse by generating elevations in intracellular Ca2+ concentration ([Ca2+](i)) and releasing glutamate that signals back to neurones. This discovery opens new perspectives for the possible participation of these glial cells in actual information processing by the brain and raises the hypothesis that astrocyte activation by neuronal signals plays a key role in distinct, functional events. Depending on the level of neuronal activity, the [Ca2+](i) response that is activated by neurotransmitters can either remain restricted to an astrocytic process or it can propagate as an intracellular [Ca2+](i) wave to other astrocytic processes in contact with different neurones, astrocytes, microglia or endothelial cells of cerebral arterioles. Glutamate release triggered by the [Ca2+](i) rise at the astrocytic process represents a feedback, short-distance signal that affects synaptic transmission locally: The release of glutamate as well as of other compounds far away from the site of initial activation represents a feedforward, long-distance signal that can be involved in the regulation of distinct processes. For instance, through the release of vasoactive molecules from the astrocytic processes in contact with cerebral arterioles, the neurone-astrocyte-endothelial cell signalling pathway plays a pivotal role in the neuronal control of vascular tone. In this article we will review recent results that should persuade us to reshape our current thinking on the roles of astroglial cells in the brain. We propose that neurones and astrocytes represent an integral unit that has a distinctive role in different fundamental events in brain function. Furthermore, while recent findings provide important evidences for the vesicular hypothesis of glutamate release, we discuss also the proposals for a possible physiological role of hemichannels and purinergic P2X(7) receptors in glutamate release from astrocytes. A full clarification of the functional significance of the bidirectional communication that astrocytes establish with neurones as well as with other brain cells represents one of the most intriguing challenges in neurobiological research at the moment and should fuel stimulating debates in years to come.