Trends in Neurosciences
ReviewAstroglia-Derived ATP Modulates CNS Neuronal Circuits
Section snippets
Purinergic Signaling by ATP in the CNS
ATP was defined as a neurotransmitter in the peripheral nervous system in a review article published as early as 1972 [1], then later as a neuroeffector (co)transmitter mediating fast and slow synaptic signals via ligand-gated cationic channels (P2X receptors, P2XRs) and G protein-coupled receptors (P2YRs), respectively 2, 3, 4, 5. P2XRs occur in native cells as homomeric (P2X1, 2, 3, 4, 5, 6, 7) and heteromeric (P2X2/3, P2X1/5) assemblies [6]. P2YRs exist in mammals as the P2Y1, 2, 4, 6, 11,
Astrocyte–Neuron Interaction
The human CNS consists of neuronal and nonneuronal cells in approximately a 1:1 relationship 12, 13. Glia constitute most of the nonneuronal cell population, but other cell types such as pericytes and endothelial cells are also part of it. The relative proportions of neurons and glia vary by region (e.g., grey vs white matter), developmental stage, and species. On the basis of morphological criteria, in the human neocortex oligodendrocytes account for ∼50–75% of the total glial population,
Exocytotic Release
It is a fascinating possibility that ATP is released in a [Ca2+]i-dependent manner exocytotically from synaptic-like vesicles of astrocytes. It was shown at first in cultured cortical and hippocampal astrocytes, by combining epifluorescence and total internal reflection fluorescence (TIRF) microscopy, that individual, quinacrine-loaded, ATP-containing vesicles undergo exocytosis 53, 54. In fact, a low percentage of fluorescently labeled vesicles displayed directional motility and underwent
Modulation of the Synaptic Plasticity of Neuronal Networks by Astrocytic ATP/ADP
In the following sections we report data obtained by a variety of techniques used to examine the modulation of neuronal circuits by astrocytic ATP/ADP (Box 1). One tool for studying gliotransmission has been dnSNARE transgenic mice in which dnSNARE is selectively overexpressed in astrocytes. In these mice, the exocytotic machinery and thereby the release of gliotransmitters is thought to be selectively impaired [41]. In hippocampal slices of wild-type (WT) mice, stimulation of Schaffer
Sleep
It has been shown that adenosine is an endogenous sleep-inducing factor. Pharmacologic inhibition of adenosine A1Rs promote wakefulness, and injecting adenosine into the brain promotes sleep 42, 46. The adenosine involved in sleep regulation appears to be of astrocytic origin, and transgenic dnSNARE mice, in which the SNARE-mediated vesicular release of gliotransmitters is inhibited, show deficits in sleep homeostasis. Although adenosine levels normally rise during wakefulness, they remain
Concluding Remarks
Only relatively few examples are known of ATP-induced and P2XR-mediated fast neuro-neuronal signaling in the CNS. However, there are many questions related to neuron-induced but astroglia-mediated modulation of neuronal circuits (see Outstanding Questions). Astroglia are endowed with several ligand-gated ion channels (e.g., P2X) and G protein-coupled receptors (e.g., P2Y) that respond to transmitter/signaling molecule stimulation and in consequence release ATP. The released ATP may
Acknowledgments
We are grateful to Ms Lumei Huang for expert drawing of the two figures. Our work was made possible by a generous grant (The Project First-Class Disciplines Development; CZYHW1901) from Chengdu University of TCM to Y.T. and P.I. to establish the International Collaborative Center for Purinergic Signaling, and grants from the Sichuan Provincial Administration of Foreign Affairs to support the stays of P.I. in Chengdu (SZD201731, SZD201846). Financial support from the National Natural Science
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