title: Adenosine released by astrocytes contributes to hypoxia-induced modulation of synaptic transmission.
abstract: Astrocytes play a critical role in brain homeostasis controlling the local environment in normal as well as in pathological conditions, such as during hypoxic/ischemic insult. Since astrocytes have recently been identified as a source for a wide variety of gliotransmitters that modulate synaptic activity, we investigated whether the hypoxia-induced excitatory synaptic depression might be mediated by adenosine release from astrocytes. We used electrophysiological and Ca2+ imaging techniques in hippocampal slices and transgenic mice, in which ATP released from astrocytes is specifically impaired, as well as chemiluminescent and fluorescence photometric Ca2+ techniques in purified cultured astrocytes. In hippocampal slices, hypoxia induced a transient depression of excitatory synaptic transmission mediated by activation of presynaptic A1 adenosine receptors. The glia-specific metabolic inhibitor fluorocitrate (FC) was as effective as the A1 adenosine receptor antagonist CPT in preventing the hypoxia-induced excitatory synaptic transmission reduction. Furthermore, FC abolished the extracellular adenosine concentration increase during hypoxia in astrocyte cultures. Several lines of evidence suggest that the increase of extracellular adenosine levels during hypoxia does not result from extracellular ATP or cAMP catabolism, and that astrocytes directly release adenosine in response to hypoxia. Adenosine release is negatively modulated by external or internal Ca2+ concentrations. Moreover, adenosine transport inhibitors did not modify the hypoxia-induced effects, suggesting that adenosine was not released by facilitated transport. We conclude that during hypoxia, astrocytes contribute to regulate the excitatory synaptic transmission through the release of adenosine, which acting on A1 adenosine receptors reduces presynaptic transmitter release. Therefore, adenosine release from astrocytes serves as a protective mechanism by down regulating the synaptic activity level during demanding conditions such as transient hypoxia.
authors.affiliation: Unidad Asociada Neurodeath, UCLM-CSIC, Departamento de Ciencias Médicas, Universidad de Castilla-La Mancha, Albacete, Spain.
authors.forename: Eduardo D
authors.initials: ED
authors.lastname: Martín
authors.forename: Miriam
authors.initials: M
authors.lastname: Fernández
authors.forename: Gertrudis
authors.initials: G
authors.lastname: Perea
authors.forename: Olivier
authors.initials: O
authors.lastname: Pascual
authors.forename: Philip G
authors.initials: PG
authors.lastname: Haydon
authors.forename: Alfonso
authors.initials: A
authors.lastname: Araque
authors.forename: Valentín
authors.initials: V
authors.lastname: Ceña
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002951:Citrates / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D002951:Citrates; D043682:Receptor, Adenosine A1; C007744:fluorocitrate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D000241:Adenosine