Impact Factor


Front. Physiol., 04 June 2012 | http://dx.doi.org/10.3389/fphys.2012.00136

Extrasynaptic neurotransmission in the modulation of brain function. Focus on the striatal neuronal–glial networks

Kjell Fuxe1*, Dasiel O. Borroto-Escuela1, Wilber Romero-Fernandez1, Zaida Diaz-Cabiale2, Alicia Rivera3, Luca Ferraro4, Sergio Tanganelli4, Alexander O. Tarakanov5, Pere Garriga6, José Angel Narváez2, Francisco Ciruela7, Michele Guescini8 and Luigi F. Agnati9
  • 1 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
  • 2 Department of Physiology, School of Medicine, University of Málaga, Málaga, Spain
  • 3 Department of Cell Biology, Faculty of Sciences, University of Málaga, Málaga, Spain
  • 4 Pharmacology Section, Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy
  • 5 Russian Academy of Sciences, St. Petersburg Institute for Informatics and Automation, Saint Petersburg, Russia
  • 6 Departament d’Enginyeria Química, Centre de Biotecnologia Molecular, Universitat Politècnica de Catalunya, Barcelona, Spain
  • 7 Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Universitat de Barcelona, Barcelona, Spain
  • 8 Department of Biomolecular Sciences, University of Urbino “CarloBo”, Urbino, Italy
  • 9 IRCCS Lido, Venice, Italy

Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT) and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR) heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT) and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT) and histamine striatal afferents, the cholinergic interneurons, and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal cellular networks.

Keywords: extrasynaptic, neurotransmission, receptor–receptor interactions, volume transmission, G protein coupled receptors, striatal networks, heteromers, wiring transission

Citation: Fuxe K, Borroto-Escuela DO, Romero-Fernandez W, Diaz-Cabiale Z, Rivera A, Ferraro L, Tanganelli S, Tarakanov AO, Garriga P, Narváez JA, Ciruela F, Guescini M and Agnati LF (2012) Extrasynaptic neurotransmission in the modulation of brain function. Focus on the striatal neuronal–glial networks. Front. Physio. 3:136. doi: 10.3389/fphys.2012.00136

Received: 24 March 2012; Paper pending published: 12 April 2012;
Accepted: 23 April 2012; Published online: 04 June 2012.

Edited by:

Francisco Fernandez De-Miguel, Universidad Nacional Autonoma de Mexico, Mexico

Reviewed by:

Francisco Fernandez De-Miguel, Universidad Nacional Autonoma de Mexico, Mexico
Teresa Giraldez, University Hospital NS Candelaria, Spain

Copyright: © 2012 Fuxe, Borroto-Escuela, Romero-Fernandez, Diaz-Cabiale, Rivera, Ferraro, Tanganelli, Tarakanov, Garriga, Narváez, Ciruela, Guescini and Agnati. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

*Correspondence: Kjell Fuxe, Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden. e-mail: kjell.fuxe@ki.se