NeuroGLIA Consortium: neuron-astroglia in brain function and dysfunction

Other consortium members

Brief description and aims of work

Our group belongs to the National Institute of Neuroscience of the National Research Council (CNR), the main public research organization in Italy, and is also associated with the Department of Experimental Biomedical Science of the University of Padua.

Since 1994 the central theme of our research is the study of the role of astroglial cells in the brain. Over the last decade our work contributed to the identification and characterization of new roles of astroglia in brain function (for reviews, see 1,3,11,12). As a multidisciplinary experimental approach, we use patch-clamp recording, laser scanning microscopy, and calcium imaging techniques in cell cultures as well as brain slice preparations.

Our overall aim is to further characterize the reciprocal communication system between neurons and astroglia.

Specific aims are the following:

• To identify the signalling molecules involved in neuron-astroglia interaction
• To define the spatial-temporal features of this signalling pathway in brain slice preparations and in vivo
• To characterize further the molecular mechanism of the astroglial control of cerebral blood flow responses
• To verify the pathological consequences in the brain of a defective neuron-astroglia signalling

Previous findings

In 1994 we showed that astroglial cells express a form of cellular memory, i.e., a property once though to be exclusive of neuronal cells (16).

In 1997 in hippocampal and visual cortex slice preparations we provided the first evidence for the ability of astroglial cells to be activated by neurotransmitter synaptic release and to signal back to neurons by releasing the gliotrasmitter glutamate (14,15).

In 2001 we confirmed that astroglial cells release glutamate through a Ca²⁺-dependent, vesicle-mediated mechanism (4,10).

In 2003 our work revealed a new function of astroglia as central mediators of functional hyperemia, i.e., the activity-dependent regulation of cerebral blood flow (9; according to ISI Thomson, Zonta et al. Nat. Neurosci. 2003, is one of the most cited recent papers in the field of Neuroscience & Behavior).

In 2004 we showed that astrocytic glutamate can generate neuronal synchrony by acting on extrasynaptic NMDA receptors (5,6). This observation represents one of the fundamental premises that lead to formulate the hypothesis of an astroglial role in epileptogenesis.

Along this line, we recently found that epileptic form activity in various brain regions (hippocampal CA3 and CA1 and somatosensory cortex) results in a strong activation of calcium oscillations and glutamate release in astroglia. We also showed that by acting on NMDARs this astroglial glutamate depolarizes neurons enough to trigger action potential firing that has the potential to contribute to the widespread, synchronous neuronal discharges typical of seizures (2,7).

Implications of our research

The emerging view attributes to astroglial cells distinct roles in important functional processes in the brain. We need now to proceed rigorously to confirm in vivo the results that have been obtained in in vitro experiments. We also need to address the intriguing possibility that a defect in the multiple actions of these glial cells contributes to the genesis and/or development of brain disorders such as epilepsy, stroke, migraine, schizophrenia and Alzheimer’s disease. Results from the new studies will clarify whether or not these cells could be potential targets for the development of novel, more efficacious, therapeutic approaches for these diseases.

Selected references

1. Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol. Rev. 86:1009-31.
2. Fellin T, Gomez-Gonzalo M, Gobbo S, Carmignoto G, Haydon PG (2006) Astrocytic glutamate is not necessary for the generation of epileptiform neuronal activity in hippocampal slices. J. Neurosci. 26:9312-22.
3. Carmignoto G, Fellin T (2006) Glutamate release from astrocytes as a non-synaptic mechanism for neuronal synchronization in the hippocampus. J. Physiol. (Paris) 99:98-102.
4. Crippa D, Schenk U, Francolini M, Rosa P, Verderio C, Zonta M, Pozzan T, Matteoli M, Carmignoto G (2006) Synaptobrevin2-expressing vesicles in rat astrocytes: insights into molecular characterization, dynamics and exocytosis. J. Physiol. (Lond.) 570:567-82.
5. Fellin T, Pozzan T, Carmignoto G (2006) Purinergic receptors mediate two distinct glutamate release pathways in hippocampal astrocytes. J. Biol. Chem. 281:4274-84.
6. Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G (2004) Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43:729-43.
7. Fellin T, Carmignoto G (2004) Neurone-to-astrocyte signalling in the brain represents a distinct multifunctional unit. J. Physiol. (Lond.) 559:3-15.
8. Zonta M, Sebelin A, Gobbo S, Fellin T, Pozzan T, Carmignoto G (2003) Glutamate-mediated cytosolic calcium oscillations regulate a pulsatile prostaglandin release from cultured rat astrocytes. J. Physiol. (Lond.) 553:407-14.
9. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat. Neurosci. 6:43-50.
10. Pasti L, Zonta M, Pozzan T, Vicini S, Carmignoto G (2001) Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate. J. Neurosci. 21:477-84.
11. Araque A, Carmignoto G, Haydon PG (2001) Dynamic signaling between astrocytes and neurons. Annu. Rev. Physiol. 63:795-813.
12. Carmignoto G (2000) Reciprocal communication systems between astrocytes and neurones. Prog. Neurobiol. 62:561-81.
13. Carmignoto G, Pasti L, Pozzan T (1998) On the role of voltage-dependent calcium channels in calcium signaling of astrocytes in situ. J. Neurosci. 18:4637-45.
14. Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391:281-5.
15. Pasti L, Volterra A, Pozzan T, Carmignoto G (1997) Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J. Neurosci. 17:7817-30.
16. Pasti L, Pozzan T, Carmignoto G (1995) Long-lasting changes of calcium oscillations in astrocytes. A new form of glutamate-mediated plasticity. J. Biol. Chem. 270:15203-10.

Past and present collaborations

• Alfonso Araque · Instituto Cajal, CSIC, Madrid, Spain
• Marco de Curtis · Clinical Epileptology and Experimental Neurophysiological Unit, Istituto Nazionale Neurologico "Carlo Besta", Milan, Italy
• Philip G. Haydon · Department of Neuroscience, University of Pennsylvania, Philadelphia, USA
• Lamberto Maffei · Scuola Normale Superiore, Pisa, Italy
• Adalberto Merighi · Department Morphophysiology, University of Turin, Grugliasco, Italy
• Michela Matteoli · Cellular and Molecular Pharmacology Center, University of Milan, Italy
• Gian Michele Ratto · Istituto CNR di Neuroscienze, Pisa, Italy
• Flora Vaccarino · Child Study Center, Yale University, New Haven, CT, USA
• Stefano Vicini · Department of Physiology and Biophysics, Georgetown University, Washington D.C., USA
• Andrea Volterra · Département de Biologie Cellulaire et de Morphologie (DBCM), Université de Lausanne, Switzerland