Journal Article

Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity

Tieu, Kim, Liu, Wei, Xu, Qiwu, Smith, Nathan A, Takano, Takahiro, Lovatt, Ditte, Nedergaard, Maiken, Schnermann, Jurgen

2012

Overview

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 Ca2+ 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: 5'-Nucleotidase / 5'-Nucleotidase - antagonists & inhibitors / 5'-Nucleotidase - genetics / 5'-Nucleotidase - metabolism / Adenosine / Adenosine - secretion / Adenosine Diphosphate / Adenosine Diphosphate - analogs & derivatives / Adenosine Diphosphate - pharmacology / adenosine monophosphate / Adenosine Monophosphate - metabolism / Adenosine triphosphatase / adenosine triphosphate / Adenosine Triphosphate - secretion / AMP / analogs & derivatives / Animals / antagonists & inhibitors / Anticonvulsants / Astrocytes / Astrocytes - metabolism / ATP / Autonomic nervous system / Biological Sciences / Brain / Brain - metabolism / Brain - physiopathology / CA1 Region, Hippocampal / CA1 Region, Hippocampal - cytology / CA1 Region, Hippocampal - metabolism / CA1 Region, Hippocampal - physiology / Calcium / Convulsions & seizures / cytology / Electrodes / Enzymes / Excitatory Postsynaptic Potentials / Excitatory Postsynaptic Potentials - physiology / Feedback inhibition / Feedback, Physiological / Feedback, Physiological - physiology / genetics / GPI-Linked Proteins / GPI-Linked Proteins - antagonists & inhibitors / GPI-Linked Proteins - genetics / GPI-Linked Proteins - metabolism / Long-Term Synaptic Depression / Long-Term Synaptic Depression - physiology / metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Neural networks / Neurons / Neurons - metabolism / Neuroscience / Neurotransmission / Patch-Clamp Techniques / pharmacology / Photolysis / physiology / physiopathology / Receptor mechanisms / Receptor, Adenosine A1 / Receptor, Adenosine A1 - metabolism / Receptors / secretion / Seizures / Seizures - metabolism / Seizures - physiopathology / synaptic depression / Synaptic transmission