Stenovec Matjaž
Celica BIOMEDICAL, Tehnološki Park 24, 1000 Ljubljana, Slovenia.
Laboratory of Neuroendocrinology-Molecular Cell Physiology, Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia.
Life (Basel). 2021 Jun 17;11(6):573. doi: 10.3390/life11060573.
Ketamine, a non-competitive -methyl-d-aspartate receptor (NMDAR) antagonist, exerts a rapid, potent and long-lasting antidepressant effect, although the cellular and molecular mechanisms of this action are yet to be clarified. In addition to targeting neuronal NMDARs fundamental for synaptic transmission, ketamine also affects the function of astrocytes, the key homeostatic cells of the central nervous system that contribute to pathophysiology of major depressive disorder. Here, I review studies revealing that (sub)anesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]) in astrocytes, attenuate stimulus-evoked astrocyte calcium signaling, which regulates exocytotic secretion of gliosignaling molecules, and stabilize the vesicle fusion pore in a narrow configuration, possibly hindering cargo discharge or vesicle recycling. Next, I discuss how ketamine affects astrocyte capacity to control extracellular K by reducing vesicular delivery of the inward rectifying potassium channel (K4.1) to the plasmalemma that reduces the surface density of Kir4.1. Modified astroglial K buffering impacts upon neuronal firing pattern as demonstrated in lateral habenula in a rat model of depression. Finally, I highlight the discovery that ketamine rapidly redistributes cholesterol in the astrocyte plasmalemma, which may alter the flux of cholesterol to neurons. This structural modification may further modulate a host of processes that synergistically contribute to ketamine's rapid antidepressant action.
氯胺酮是一种非竞争性 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，具有快速、强效且持久的抗抑郁作用，尽管其作用的细胞和分子机制尚待阐明。除了作用于对突触传递至关重要的神经元 NMDAR 外，氯胺酮还会影响星形胶质细胞的功能，星形胶质细胞是中枢神经系统中关键的稳态细胞，参与重度抑郁症的病理生理过程。在此，我回顾了一些研究，这些研究表明，（亚）麻醉剂量的氯胺酮可提高星形胶质细胞内的细胞内 cAMP 浓度（[cAMP]），减弱刺激诱发的星形胶质细胞钙信号传导（该信号传导调节胶质信号分子的胞吐分泌），并使囊泡融合孔稳定在狭窄构型，这可能会阻碍货物释放或囊泡循环利用。接下来，我将讨论氯胺酮如何通过减少内向整流钾通道（K4.1）向质膜的囊泡转运来影响星形胶质细胞控制细胞外钾的能力，而这种转运减少了 Kir4.1 的表面密度。如在抑郁症大鼠模型的外侧缰核中所证实的，星形胶质细胞钾缓冲功能的改变会影响神经元的放电模式。最后，我强调了一项发现，即氯胺酮可使星形胶质细胞质膜中的胆固醇迅速重新分布，这可能会改变胆固醇向神经元的通量。这种结构修饰可能会进一步调节一系列协同促成氯胺酮快速抗抑郁作用的过程。
