Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures

Originally ascribed passive roles in the CNS, astrocytes are now known to have an active role in the regulation of synaptic transmission. Neuronal activity can evoke Ca2+ transients in astrocytes, and Ca2+ transients in astrocytes can evoke changes in neuronal activity. The excitatory neurotransmitter glutamate has been shown to mediate such bidirectional communication between astrocytes and neurons. We demonstrate here that ATP, a primary mediator of intercellular Ca2+ signaling among astrocytes, also mediates intercellular signaling between astrocytes and neurons in hippocampal cultures. Mechanical stimulation of astrocytes evoked Ca2+ waves mediated by the release of ATP and the activation of P2 receptors. Mechanically evoked Ca2+ waves led to decreased excitatory glutamatergic synaptic transmission in an ATP-dependent manner. Exogenous application of ATP does not affect postsynaptic glutamatergic responses but decreased presynaptic exocytotic events. Finally, we show that astrocytes exhibit spontaneous Ca2+ waves mediated by extracellular ATP and that inhibition of these Ca2+ responses enhanced excitatory glutamatergic transmission. We therefore conclude that ATP released from astrocytes exerts tonic and activity-dependent down-regulation of synaptic transmission via presynaptic mechanisms.

[1]  M. Matteoli,et al.  Storage and Release of ATP from Astrocytes in Culture* , 2003, The Journal of Biological Chemistry.

[2]  S. Koizumi,et al.  Spatial and temporal aspects of Ca2+ signaling mediated by P2Y receptors in cultured rat hippocampal astrocytes. , 2002, Life sciences.

[3]  Y. Kuroda,et al.  Hetero‐oligomerization of adenosine A1 receptors with P2Y1 receptors in rat brains , 2002, FEBS letters.

[4]  J. Roder,et al.  Mechanisms Underlying the Neuronal Calcium Sensor-1-evoked Enhancement of Exocytosis in PC12 Cells* , 2002, The Journal of Biological Chemistry.

[5]  C. Naus,et al.  Intercellular Calcium Signaling in Astrocytes via ATP Release through Connexin Hemichannels* , 2002, The Journal of Biological Chemistry.

[6]  H. Nakata,et al.  Heteromeric association creates a P2Y-like adenosine receptor , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  P. Haydon.  Glia: listening and talking to the synapse , 2001, Nature Reviews Neuroscience.

[8]  M. Salter,et al.  P2Y1 Purinoceptor-Mediated Ca2+ Signaling and Ca2+ Wave Propagation in Dorsal Spinal Cord Astrocytes , 2000, The Journal of Neuroscience.

[9]  M. Nedergaard,et al.  ATP-Mediated Glia Signaling , 2000, The Journal of Neuroscience.

[10]  R. Andrew,et al.  ATP inhibits glutamate synaptic release by acting at P2Y receptors in pyramidal neurons of hippocampal slices. , 2000, The Journal of pharmacology and experimental therapeutics.

[11]  Z Wang,et al.  Direct observation of calcium-independent intercellular ATP signaling in astrocytes. , 2000, Analytical chemistry.

[12]  T. Laverty,et al.  Response of Schwann cells to action potentials in development. , 2000, Science.

[13]  M. Berridge,et al.  Characterization of Elementary Ca2+ Release Signals in NGF-Differentiated PC12 Cells and Hippocampal Neurons , 1999, Neuron.

[14]  S. B. Kater,et al.  ATP Released from Astrocytes Mediates Glial Calcium Waves , 1999, The Journal of Neuroscience.

[15]  C. Naus,et al.  Connexins regulate calcium signaling by controlling ATP release. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Goldman,et al.  Astrocyte-mediated potentiation of inhibitory synaptic transmission , 1998, Nature Neuroscience.

[17]  K. Zahs,et al.  Modulation of Neuronal Activity by Glial Cells in the Retina , 1998, The Journal of Neuroscience.

[18]  A. Araque,et al.  Glutamate‐dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons , 1998, The European journal of neuroscience.

[19]  R. Cunha,et al.  Inhibition by ATP of Hippocampal Synaptic Transmission Requires Localized Extracellular Catabolism by Ecto-Nucleotidases into Adenosine and Channeling to Adenosine A1 Receptors , 1998, The Journal of Neuroscience.

[20]  Tullio Pozzan,et al.  Prostaglandins stimulate calcium-dependent glutamate release in astrocytes , 1998, Nature.

[21]  T. Pozzan,et al.  Intracellular Calcium Oscillations in Astrocytes: A Highly Plastic, Bidirectional Form of Communication between Neurons and Astrocytes In Situ , 1997, The Journal of Neuroscience.

[22]  S. Koizumi,et al.  Inhibition by ATP of calcium oscillations in rat cultured hippocampal neurones , 1997, British journal of pharmacology.

[23]  K. Starke,et al.  P2-Receptor-mediated inhibition of noradrenaline release in the rat hippocampus , 1997, Naunyn-Schmiedeberg's Archives of Pharmacology.

[24]  K. Zahs,et al.  Calcium Waves in Retinal Glial Cells , 1997, Science.

[25]  S. Jeftinija,et al.  Neuroligand‐Evoked Calcium‐Dependent Release of Excitatory Amino Acids from Cultured Astrocytes , 1996, Journal of neurochemistry.

[26]  H. Reuter,et al.  Localization and functional significance of the Na+/Ca2+exchanger in presynaptic boutons of hippocampal cells in culture , 1995, Neuron.

[27]  S. Koizumi,et al.  Zinc potentiation of neurotransmission and inhibition of background cationic conductance in rat cultured hippocampal neurones. , 1995, The Journal of physiology.

[28]  Fang Liu,et al.  Glutamate-mediated astrocyte–neuron signalling , 1994, Nature.

[29]  M. Nedergaard,et al.  Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. , 1994, Science.

[30]  M. Salter,et al.  ATP-evoked increases in intracellular calcium in neurons and glia from the dorsal spinal cord , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  F. Edwards,et al.  ATP receptor-mediated synaptic currents in the central nervous system , 1992, Nature.

[32]  A. Ogura,et al.  Optical monitoring of excitatory synaptic activity between cultured hippocampal neurons by a multi-site Ca2+ fluorometry , 1987, Neuroscience Letters.

[33]  Babu Subramanyam,et al.  MONITORING MOLECULES IN NEUROSCIENCE , 1991 .