Celica BIOMEDICAL, Tehnološki Park 24, 1000, Ljubljana, Slovenia; Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000, Ljubljana, Slovenia.
Practical Teaching Centre, School of Forensic Medicine, China Medical University, Shenyang, People's Republic of China; Department of Poison Analysis, School of Forensic Medicine, China Medical University, Shenyang, China.
Neuropharmacology. 2020 Aug 15;173:108158. doi: 10.1016/j.neuropharm.2020.108158. Epub 2020 May 25.
Ketamine, a general anaesthetic and psychotomimetic drug, exerts rapid, potent and long-lasting antidepressant effect, albeit the cellular and molecular mechanisms of this action are yet to be discovered. Besides targeting neuronal NMDARs fundamental for synaptic transmission, ketamine affects the function of astroglia the key homeostatic cells of the central nervous system that contribute to pathophysiology of psychiatric diseases including depression. Here we review studies revealing that (sub)anaesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]) in astrocytes, attenuate stimulus-evoked astrocyte calcium signalling, which regulates exocytotic secretion of gliosignalling molecules, and stabilize the vesicle fusion pore in a narrow configuration possibly hindering cargo discharge or vesicle recycling. Next we discuss how ketamine affects astroglial capacity to control extracellular K by reducing cytoplasmic mobility of vesicles delivering the inward rectifying potassium channel (Kir4.1) to the plasmalemma. Modified astroglial K buffering impacts upon neuronal excitability as demonstrated in the lateral habenula rat model of depression. Finally, we highlight the recent discovery that ketamine rapidly redistributes cholesterol in the plasmalemma of astrocytes, but not in fibroblasts nor in neuronal cells. This alteration of membrane structure may modulate a host of processes that synergistically contribute to ketamine's rapid and prominent antidepressant action.
氯胺酮是一种全身麻醉剂和致幻药物，具有快速、强效和持久的抗抑郁作用，但这种作用的细胞和分子机制尚未被发现。除了靶向神经元 NMDARs（对突触传递至关重要）外，氯胺酮还影响星形胶质细胞的功能，星形胶质细胞是中枢神经系统的关键稳态细胞，对包括抑郁症在内的精神疾病的病理生理学有贡献。在这里，我们回顾了一些研究，这些研究表明，（亚）麻醉剂量的氯胺酮会增加星形胶质细胞内的 cAMP 浓度 ([cAMP])，减弱刺激诱发的星形胶质细胞钙信号，从而调节神经胶质信号分子的胞吐分泌，并稳定融合孔在狭窄的构象，可能阻碍货物排放或囊泡再循环。接下来，我们讨论氯胺酮如何通过减少内向整流钾通道 (Kir4.1) 向质膜运输的囊泡的细胞质流动性，来影响星形胶质细胞控制细胞外 K 的能力。在抑郁症的外侧缰核大鼠模型中，已经证明了经修饰的星形胶质细胞 K 缓冲作用对神经元兴奋性的影响。最后，我们强调了最近的发现，即氯胺酮可快速重新分布星形胶质细胞质膜中的胆固醇，但不会在成纤维细胞或神经元细胞中重新分布。这种膜结构的改变可能调节一系列协同促进氯胺酮快速和显著抗抑郁作用的过程。
