An autocrine purinergic signaling controls astrocyte-induced neuronal excitation

Weida Shen,Ljiljana Nikolic,Claire Meunier,Frank Pfrieger,Etienne Audinat

doi:10.1038/s41598-017-11793-x

Abstract

Astrocyte-derived gliotransmitters glutamate and ATP modulate neuronal activity. It remains unclear, however, how astrocytes control the release and coordinate the actions of these gliotransmitters. Using transgenic expression of the light-sensitive channelrhodopsin 2 (ChR2) in astrocytes, we observed that photostimulation reliably increases action potential firing of hippocampal pyramidal neurons. This excitation relies primarily on a calcium-dependent glutamate release by astrocytes that activates neuronal extra-synaptic NMDA receptors. Remarkably, our results show that ChR2-induced Ca2+ increase and subsequent glutamate release are amplified by ATP/ADP-mediated autocrine activation of P2Y1 receptors on astrocytes. Thus, neuronal excitation is promoted by a synergistic action of glutamatergic and autocrine purinergic signaling in astrocytes. This new mechanism may be particularly relevant for pathological conditions in which ATP extracellular concentration is increased and acts as a major danger signal.

Highlights

Astrocytes are the most abundant type of glial cells of the central nervous system and their position between blood vessels and synapses allows them to fulfill metabolic and homeostatic functions that are essential for the proper functioning of neuronal networks[1]
In order to study the consequences of astrocyte stimulation on neuronal activity we used a transgenic approach aiming at expressing light-sensitive channelrhodopsin 2 (ChR2) in astrocytes
We observed that a majority of astrocytes identified by the specific markers glutamine synthase (GS; Fig. 1a) or glial fibrillary acidic protein (GFAP; Supplementary Fig. 1b) were positive for EYFP and likely expressed ChR2

Summary

Introduction

Astrocytes are the most abundant type of glial cells of the central nervous system and their position between blood vessels and synapses allows them to fulfill metabolic and homeostatic functions that are essential for the proper functioning of neuronal networks[1]. We have used a transgenic approach to express ChR2 in hippocampal astrocytes in a highly specific, widespread and reliable manner In this model, blue light stimulation reliably triggered time-locked Ca2+ elevations in astrocytes and subsequent glutamate release that targets neuronal receptors. Blue light stimulation reliably triggered time-locked Ca2+ elevations in astrocytes and subsequent glutamate release that targets neuronal receptors This astrocyte glutamate release is tightly controlled by an autocrine mechanism involving ATP release and P2Y1R activation. This synergistic action of purinergic and glutamatergic signaling in astrocyte promote neuronal excitation

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Results

Conclusion