Multiple Lines of Evidence Indicate That Gliotransmission Does Not Occur under Physiological Conditions

Abstract

A major controversy persists within the field of glial biology concerning whether or not, under physiological conditions, neuronal activity leads to Ca²⁺-dependent release of neurotransmitters from astrocytes, a phenomenon known as gliotransmission. Our perspective is that, while we and others can apply techniques to cause gliotransmission, there is considerable evidence gathered using astrocyte-specific and more physiological approaches which suggests that gliotransmission is a pharmacological phenomenon rather than a physiological process. Approaches providing evidence against gliotransmission include stimulation of Gq-GPCRs expressed only in astrocytes, as well as removal of the primary proposed source of astrocyte Ca²⁺ responsible for gliotransmission. These approaches contrast with those supportive of gliotransmission, which include mechanical stimulation, strong astrocytic depolarization using whole-cell patch-clamp or optogenetics, uncaging Ca²⁺ or IP3, chelating Ca²⁺ using BAPTA, and nonspecific bath application of agonists to receptors expressed by a multitude of cell types. These techniques are not subtle and therefore are not supportive of recent suggestions that gliotransmission requires very specific and delicate temporal and spatial requirements. Other evidence, including lack of propagating Ca²⁺ waves between astrocytes in healthy tissue, lack of expression of vesicular release machinery, and the demise of the d-serine gliotransmission hypothesis, provides additional evidence against gliotransmission. Overall, the data suggest that Ca²⁺-dependent release of neurotransmitters is the province of neurons, not astrocytes, in the intact brain under physiological conditions.Dual Perspectives Companion Paper: Gliotransmission: Beyond Black-and-White, by Iaroslav Savtchouk and Andrea Volterra.

Keywords: GPCR; IP3R; astrocyte; calcium; d-serine; glutamate.