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Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex
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Lalo, Ulyana, Palygin, Oleg, Rasooli-Nejad, Seyed, Andrew, Jemma, Haydon, Philip G. and Pankratov, Yuriy (2014) Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biology, Volume 12 (Number 1). Article number e1001747. doi:10.1371/journal.pbio.1001747 ISSN 1545-7885.
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Official URL: http://dx.doi.org/10.1371/journal.pbio.1001747
Abstract
Communication between neuronal and glial cells is important for many brain functions. Astrocytes can modulate synaptic strength via Ca2+-stimulated release of various gliotransmitters, including glutamate and ATP. A physiological role of ATP release from astrocytes was suggested by its contribution to glial Ca2+-waves and purinergic modulation of neuronal activity and sleep homeostasis. The mechanisms underlying release of gliotransmitters remain uncertain, and exocytosis is the most intriguing and debated pathway. We investigated release of ATP from acutely dissociated cortical astrocytes using “sniff-cell” approach and demonstrated that release is vesicular in nature and can be triggered by elevation of intracellular Ca2+ via metabotropic and ionotropic receptors or direct UV-uncaging. The exocytosis of ATP from neocortical astrocytes occurred in the millisecond time scale contrasting with much slower nonvesicular release of gliotransmitters via Best1 and TREK-1 channels, reported recently in hippocampus. Furthermore, we discovered that elevation of cytosolic Ca2+ in cortical astrocytes triggered the release of ATP that directly activated quantal purinergic currents in the pyramidal neurons. The glia-driven burst of purinergic currents in neurons was followed by significant attenuation of both synaptic and tonic inhibition. The Ca2+-entry through the neuronal P2X purinoreceptors led to phosphorylation-dependent down-regulation of GABAA receptors. The negative purinergic modulation of postsynaptic GABA receptors was accompanied by small presynaptic enhancement of GABA release. Glia-driven purinergic modulation of inhibitory transmission was not observed in neurons when astrocytes expressed dn-SNARE to impair exocytosis. The astrocyte-driven purinergic currents and glia-driven modulation of GABA receptors were significantly reduced in the P2X4 KO mice. Our data provide a key evidence to support the physiological importance of exocytosis of ATP from astrocytes in the neocortex.
Item Type: | Journal Article | ||||||||
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Subjects: | Q Science > QP Physiology | ||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||
Library of Congress Subject Headings (LCSH): | Exocytosis, Astrocytes, Neocortex, Adenosine triphosphate | ||||||||
Journal or Publication Title: | PLoS Biology | ||||||||
Publisher: | Public Library of Science | ||||||||
ISSN: | 1545-7885 | ||||||||
Official Date: | 7 January 2014 | ||||||||
Dates: |
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Volume: | Volume 12 | ||||||||
Number: | Number 1 | ||||||||
Article Number: | Article number e1001747 | ||||||||
DOI: | 10.1371/journal.pbio.1001747 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||
Date of first compliant deposit: | 26 December 2015 | ||||||||
Date of first compliant Open Access: | 26 December 2015 | ||||||||
Funder: | Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), University of Warwick | ||||||||
Grant number: | BB/F021445 (BBSRC), BB/K009192 (BBSRC), RD11153 (UoW) |
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