Astrocytes promote ethanol-induced enhancement of intracellular Ca2+ signals through intercellular communication with neurons

Ethanol (EtOH) abuse induces significant mortality and morbidity worldwide because of detrimental effects on brain function. Defining the contribution of astrocytes to this malfunction is imperative to understanding the overall EtOH effects due to their role in homeostasis and EtOH-seeking behaviors. Using a highly controllable in vitro system, we identify chemical signaling mechanisms through which acute EtOH exposure induces a modulatory feedback loop between neurons and astrocytes. Neuronally-derived purinergic signaling primed a subpopulation of astrocytes to respond to subsequent acute EtOH exposures (SEastrocytes: signal enhanced astrocytes) with greater calcium signal strength. Generation of SEastrocytes arose from astrocytic hemichannel-derived ATP and accumulation of its metabolite adenosine within the astrocyte microenvironment to modulate adenylyl cyclase and phospholipase C activity. These results highlight an important role of astrocytes in shaping the overall physiological responsiveness to EtOH and emphasize the unique plasticity of astrocytes to adapt to single and multiple exposures of EtOH. [Display omitted] •Ethanol elicits [Ca2+]i signals in astrocytes and neurons using different mechanisms•Astrocyte hemichannel-dependent ATP release facilitates [Ca2+]i signaling by ethanol•Ethanol induces intercellular signaling between astrocytes and neurons•Intercellular signaling enhances [Ca2+]i signals in astrocyte and neuron subgroups