title: Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity.
abstract: Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of adenosine remains unclear. We report here that multiple enzymes degrade extracellular ATP in brain tissue, whereas only Nt5e degrades AMP to adenosine. However, endogenous A1 receptor activation during cortical seizures in vivo or heterosynaptic depression in situ is independent of Nt5e activity, and activation of astrocytic ATP release via Ca(2+) photolysis does not trigger synaptic depression. In contrast, selective activation of postsynaptic CA1 neurons leads to release of adenosine and synaptic depression. This study shows that adenosine-mediated synaptic depression is not a consequence of astrocytic ATP release, but is instead an autonomic feedback mechanism that suppresses excitatory transmission during prolonged activity.
authors.affiliation: Center for Translational Neuromedicine, Departments of Neurosurgery and Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Ditte
authors.initials: D
authors.lastname: Lovatt
authors.forename: Qiwu
authors.initials: Q
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takano
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Smith
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schnermann
authors.forename: Kim
authors.initials: K
authors.lastname: Tieu
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D012640:Seizures / Q000378:metabolism / Q000503:physiopathology
chemical_list: D058851:GPI-Linked Proteins; D043682:Receptor, Adenosine A1; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; C548242:Nt5e protein, mouse; D000241:Adenosine