The characterization of the specific communication system existing in the brain between neurons and astrocytes represents the main research goal of our group. After the initial finding that astrocytes from brain slices are sensitive to the synaptic release of glutamate, our research is now focused on the clarification of the distinct roles of this novel signalling pathway in brain function. To this aim, we use both acute brain slice preparations as well as cell cultures, adopting different experimental approaches, such as patch clamp recording and confocal microscopy for calcium imaging at the single cell level. Using these techniques, we recently described a distinct role of neuron-to-astrocyte communication in the coupling between neuronal activity and blood flow - the so-called functional hyperemia.
In a first series of experiments, we characterised the response of astrocytes in culture to the neurotransmitter glutamate – we were able to demonstrate that these glial cells display a plasticity of response to repetitive stimulation with glutamate [1]. The observation that astrocytes display a form of cellular memory – previously believed to be an exclusive property of neuronal cells – led us to hypothesize a specific role of astrocytes in brain function [2]. Using hippocampal cortical slices, we obtained the first evidence of a specific communication pathway between neurons and astrocytes, mediated by a common agent: glutamate. The synaptic release of glutamate was found to activate metabotropic glutamate receptors (specifically, type I) on the astrocytic membrane, evoking the elevation of intracellular calcium in these cells [2,3]. We then demonstrated that astrocytes themselves can release glutamate; this, in turn, can activate ionotropic glutamate receptors in nearby neurones, evoking significant calcium elevations in these cells [3,4]. Contrary to what happens in neurones, the astrocyte glutamate release appeared not to depend on calcium influx through voltage-dependent calcium channels [5], but rather on calcium release from intracellular stores. More recently, we obtained a series of information on the mechanism, the signal transduction system, and the spatio-temporal features of glutamate release from astrocytes [4,6,7]. These studies – together with those from other groups [8,9] – demonstrated the existence of a reciprocal communication system between neurones and astrocytes that allow these cells to exchange information and probably transfer long-distance messages [10].
We are only now beginning to understand the complex role that this novel signalling pathway may have in brain function. Some experimental evidence hints at a role of glutamate release from astrocytes in the modulation of neuronal transmission. Astrocytes appear also to affect the development and maturation of synaptic connections [11]. After some initial hesitations, the scientific community seems to have now accepted an active role of these glial cells in brain processes once believed to be exclusive tasks of neurones. Our contribution to the revision of the astrocyte role in the brain is summarized in recently published reviews [11-13].
REFERENCES
- Pasti L., Pozzan T. and Carmignoto G. (1995) Long-lasting changes of calcium oscillations in astrocytes: a new form of glutamate-mediated plasticity. J. Biol. Chem. 270, 15203-15210.
- Carmignoto G., Pasti L. and Pozzan T. (1999) Intracellular calcium pools and calcium oscillations in cells from the central nervous system. In: "Calcium as a cellular regulator". Eds Carafoli E. and Klee C., Oxford University Press, pp. 55-70.
- Pasti L, Volterra A, Pozzan T and Carmignoto G. (1997) Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J Neurosci. 17, 7817-7830.
- Bezzi P., Carmignoto G., Pasti L, Vesce S, Rossi D., Lodi Rizzini B, Pozzan T. and Volterra A. (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391, 281-285.
- Carmignoto G., Pasti L. and Pozzan T. (1998) On the Role of Voltage-Dependent Calcium Channels in Calcium Signalling of Astrocytes in situ. J. Neurosci. 18, 4637-4645.
- Pasti L., Zonta M., Pozzan T., Vicini S. and Carmignoto G. (2001) Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate. J. Neurosci. 21, 477-484.
- Carmignoto G. (2000) Astrocyte-neuron cross-talk: variants of the same language? Trends in Pharmacol. Sci. 21, 373-374.
- Parpura, V., Basarky, T. A., Liu, F., Jeftinija, K., Jeftinija, S. and Haydon, P.G. (1994) Glutamate-mediated astrocyte-neurone signalling. Nature 369, 744-747.
- Araque, A., Li, N., Doyle, R. T. and Haydon, P. G. (2000) Snare protein-dependent glutamate release from astrocytes. J. Neurosci. 20, 666-673.
- Carmignoto G. (2000) Bidirectional communication between neurones and astrocytes. Progress in Neurobiol. 62, 561-581.
- Ullian et al., (2001) Control of synapse number by glia. Science 291, 657-66010.
- Haydon P.G. (2001) Glia: listening and talking to the synapse. Nature Review Neurosci. 2, 185-193.
- Araque A., Carmignoto G. and Haydon P.G. (2001) Dynamic signaling between astrocytes and neurons. Ann. Rev. Physiol. 63, 795-813.
The contents of this frame, © Giorgio Carmignoto, March 2003
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