Department of Morphological Sciences, Federal University of Rio Grande Do Sul, Sarmento Leite Street, 500, CEP 90050-170, Porto Alegre, Brazil.
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, Japan.
J Pharmacol Sci. 2021 Jan;145(1):60-68. doi: 10.1016/j.jphs.2020.11.002. Epub 2020 Nov 11.
Emerging evidence suggests that dysfunctions in glutamatergic signaling are associated with the pathophysiology of depression. Several molecules that act on glutamate binding sites, so-called glutamatergic modulators, are rapid-acting antidepressants that stimulate synaptogenesis. Their antidepressant response involves the elevation of both extracellular glutamate and brain-derived neurotrophic factor (BDNF) levels, as well as the postsynaptic activation of the mammalian target of rapamycin complex 1. The mechanisms involved in the antidepressant outcomes of glutamatergic modulators, including ketamine, suggest that astrocytes must be considered a cellular target for developing rapid-acting antidepressants. It is well known that extracellular glutamate levels and glutamate intrasynaptic time-coursing are maintained by perisynaptic astrocytes, where inwardly rectifying potassium channels 4.1 (Kir4.1 channels) regulate both potassium and glutamate uptake. In addition, ketamine reduces membrane expression of Kir4.1 channels, which raises extracellular potassium and glutamate levels, increasing postsynaptic neural activities. Furthermore, inhibition of Kir4.1 channels stimulates BDNF expression in astrocytes, which may enhance synaptic connectivity. In this review, we discuss glutamatergic modulators' actions in regulating extracellular glutamate and BDNF levels, and reinforce the importance of perisynaptic astrocytes for the development of novel antidepressant drugs.
新出现的证据表明，谷氨酸能信号传导功能障碍与抑郁症的病理生理学有关。几种作用于谷氨酸结合位点的分子，即所谓的谷氨酸调节剂，是快速作用的抗抑郁药，可刺激突触发生。它们的抗抑郁反应涉及细胞外谷氨酸和脑源性神经营养因子 (BDNF) 水平的升高，以及哺乳动物雷帕霉素靶蛋白复合物 1 的突触后激活。包括氯胺酮在内的谷氨酸调节剂的抗抑郁作用机制表明，星形胶质细胞必须被视为开发快速作用抗抑郁药的细胞靶标。众所周知，细胞外谷氨酸水平和谷氨酸突触内时间进程由突触旁星形胶质细胞维持，其中内向整流钾通道 4.1 (Kir4.1 通道) 调节钾和谷氨酸的摄取。此外，氯胺酮降低 Kir4.1 通道的膜表达，从而提高细胞外钾和谷氨酸水平，增加突触后神经活动。此外，抑制 Kir4.1 通道可刺激星形胶质细胞中 BDNF 的表达，从而增强突触连接。在这篇综述中，我们讨论了谷氨酸调节剂在调节细胞外谷氨酸和 BDNF 水平方面的作用，并强调了突触旁星形胶质细胞在开发新型抗抑郁药物中的重要性。
