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Nitric Oxide–mediated Modulation of Synaptic Activity by Astrocytic P2Y Receptors

Nitric Oxide–mediated Modulation of Synaptic Activity by Astrocytic P2Y Receptors We investigated the mechanism of synaptic suppression by P2Y receptors in mixed hippocampal cultures wherein networked neurons exhibit synchronized Ca 2+ oscillations (SCO) due to spontaneous glutamatergic synaptic transmission. Pharmacological studies suggested that SCO suppression was mediated by P2Y2/P2Y4 receptors. Immunostaining studies and characterization of ATP/UTP-stimulated Ca 2+ responses in solitary neurons and astrocytes revealed that the SCO attenuation was effectuated by astrocytes. We demonstrate that nitric oxide released from activated astrocytes causes synaptic suppression by inhibiting neurotransmitter release. Physiological concentrations of ATP and UTP evoked NO production in astrocytes. SCO suppression was considerably diminished by removal of extracellular NO by membrane-impermeable scavenger c-PTIO or by pretreatment of cells with nitric oxide synthase inhibitor L-NAME. The nitric oxide donor DETA/NO effectively suppressed the SCO. ATP/UTP inhibited KCl-induced exocytosis at presynaptic terminals in an NO-dependent manner. In the absence of exogenously added ATP/UTP, both the NO scavenger and NOS inhibitor enhanced the frequency of SCO, implying that astrocytes release NO during spontaneous synaptic activity and exert a suppressive effect. We report for the first time that under physiological conditions astrocytes use NO as a messenger molecule to modulate the synaptic strength in the networked neurons. Footnotes Abbreviations used in this paper: APV, 2-amino-5-phosphonopentanoic acid; CNQX, 6-cyano-7-nitroquinozaline-2,3-dione; DAF-DA, diaminofluorescein diacetate; DETA-NO, (Z)-1- N -(2-aminoethyl)- N -(2-ammonioethyl) amino diazen-1-ium-1,2-diolate; ROI, region of interest. © 2008 Mehta et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ). Submitted: 14 May 2008 Accepted: 28 July 2008 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of General Physiology Rockefeller University Press

Nitric Oxide–mediated Modulation of Synaptic Activity by Astrocytic P2Y Receptors

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Publisher
Rockefeller University Press
Copyright
© 2008 Mehta et al.
ISSN
0022-1295
eISSN
1540-7748
DOI
10.1085/jgp.200810043
pmid
18725529
Publisher site
See Article on Publisher Site

Abstract

We investigated the mechanism of synaptic suppression by P2Y receptors in mixed hippocampal cultures wherein networked neurons exhibit synchronized Ca 2+ oscillations (SCO) due to spontaneous glutamatergic synaptic transmission. Pharmacological studies suggested that SCO suppression was mediated by P2Y2/P2Y4 receptors. Immunostaining studies and characterization of ATP/UTP-stimulated Ca 2+ responses in solitary neurons and astrocytes revealed that the SCO attenuation was effectuated by astrocytes. We demonstrate that nitric oxide released from activated astrocytes causes synaptic suppression by inhibiting neurotransmitter release. Physiological concentrations of ATP and UTP evoked NO production in astrocytes. SCO suppression was considerably diminished by removal of extracellular NO by membrane-impermeable scavenger c-PTIO or by pretreatment of cells with nitric oxide synthase inhibitor L-NAME. The nitric oxide donor DETA/NO effectively suppressed the SCO. ATP/UTP inhibited KCl-induced exocytosis at presynaptic terminals in an NO-dependent manner. In the absence of exogenously added ATP/UTP, both the NO scavenger and NOS inhibitor enhanced the frequency of SCO, implying that astrocytes release NO during spontaneous synaptic activity and exert a suppressive effect. We report for the first time that under physiological conditions astrocytes use NO as a messenger molecule to modulate the synaptic strength in the networked neurons. Footnotes Abbreviations used in this paper: APV, 2-amino-5-phosphonopentanoic acid; CNQX, 6-cyano-7-nitroquinozaline-2,3-dione; DAF-DA, diaminofluorescein diacetate; DETA-NO, (Z)-1- N -(2-aminoethyl)- N -(2-ammonioethyl) amino diazen-1-ium-1,2-diolate; ROI, region of interest. © 2008 Mehta et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ). Submitted: 14 May 2008 Accepted: 28 July 2008

Journal

The Journal of General PhysiologyRockefeller University Press

Published: Sep 1, 2008

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