Faculty Collaboration Database

Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biol 2014 Jan;12(1):e1001747

Date

01/11/2014

Pubmed ID

24409095

Pubmed Central ID

PMC3883644

DOI

10.1371/journal.pbio.1001747

Scopus ID

2-s2.0-84893729051 (requires institutional sign-in at Scopus site)   224 Citations

Abstract

Communication between neuronal and glial cells is important for many brain functions. Astrocytes can modulate synaptic strength via Ca(2+)-stimulated release of various gliotransmitters, including glutamate and ATP. A physiological role of ATP release from astrocytes was suggested by its contribution to glial Ca(2+)-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 Ca(2+) 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 Ca(2+) 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 Ca(2+)-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.

Author List

Lalo U, Palygin O, Rasooli-Nejad S, Andrew J, Haydon PG, Pankratov Y

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Astrocytes
Bestrophins
Calcium
Cell Communication
Exocytosis
Eye Proteins
Gene Expression Regulation
Glutamic Acid
Ion Channels
Membrane Potentials
Mice
Mice, Transgenic
Neocortex
Neural Inhibition
Neurons
Patch-Clamp Techniques
Potassium Channels, Tandem Pore Domain
Receptors, GABA-A
Receptors, Purinergic P2X4
SNARE Proteins
Synaptic Transmission
gamma-Aminobutyric Acid