Kim Hyun-Bum, Morris Jacqueline, Miyashiro Kevin, Lehto Tõnis, Langel Ülo, Eberwine James, Sul Jai-Yoon
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Biochemistry and Biophysics, The Arrhenius Laboratories for Natural Sciences, Stockholm University, Svante Arrhenius väg 16B, 10691, Stockholm, Sweden.
iScience. 2021 Apr 17;24(5):102436. doi: 10.1016/j.isci.2021.102436. eCollection 2021 May 21.
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 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 (astrocytes: signal enhanced astrocytes) with greater calcium signal strength. Generation of astrocytes 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.
乙醇（EtOH）滥用在全球范围内导致了显著的死亡率和发病率，因为它对脑功能有有害影响。由于星形胶质细胞在体内平衡和寻求乙醇行为中所起的作用，确定其对这种功能障碍的作用对于理解乙醇的整体影响至关重要。我们使用一个高度可控的系统，确定了化学信号传导机制，急性乙醇暴露通过该机制在神经元和星形胶质细胞之间诱导一个调节反馈回路。神经元衍生的嘌呤能信号使一部分星形胶质细胞对随后的急性乙醇暴露（星形胶质细胞：信号增强型星形胶质细胞）产生反应，其钙信号强度更大。星形胶质细胞的产生源于星形胶质细胞半通道衍生的ATP及其代谢产物腺苷在星形胶质细胞微环境中的积累，以调节腺苷酸环化酶和磷脂酶C的活性。这些结果突出了星形胶质细胞在塑造对乙醇的整体生理反应中的重要作用，并强调了星形胶质细胞适应单次和多次乙醇暴露的独特可塑性。
