Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA.
Neuropharmacology. 2021 Sep 15;196:108719. doi: 10.1016/j.neuropharm.2021.108719. Epub 2021 Jul 15.
Glutamate is the primary excitatory neurotransmitter of the brain. Cellular homeostasis of glutamate is of paramount importance for normal brain function and relies on an intricate metabolic collaboration between neurons and astrocytes. Glutamate is extensively recycled between neurons and astrocytes in a process known as the glutamate-glutamine cycle. The recycling of glutamate is closely linked to brain energy metabolism and is essential to sustain glutamatergic neurotransmission. However, a considerable amount of glutamate is also metabolized and serves as a metabolic hub connecting glucose and amino acid metabolism in both neurons and astrocytes. Disruptions in glutamate clearance, leading to neuronal overstimulation and excitotoxicity, have been implicated in several neurodegenerative diseases. Furthermore, the link between brain energy homeostasis and glutamate metabolism is gaining attention in several neurological conditions. In this review, we provide an overview of the dynamics of synaptic glutamate homeostasis and the underlying metabolic processes with a cellular focus on neurons and astrocytes. In particular, we review the recently discovered role of neuronal glutamate uptake in synaptic glutamate homeostasis and discuss current advances in cellular glutamate metabolism in the context of Alzheimer's disease and Huntington's disease. Understanding the intricate regulation of glutamate-dependent metabolic processes at the synapse will not only increase our insight into the metabolic mechanisms of glutamate homeostasis, but may reveal new metabolic targets to ameliorate neurodegeneration.
谷氨酸是大脑中主要的兴奋性神经递质。谷氨酸的细胞内稳态对于正常的大脑功能至关重要，这依赖于神经元和星形胶质细胞之间复杂的代谢协作。谷氨酸在神经元和星形胶质细胞之间广泛地进行循环回收，这个过程被称为谷氨酸-谷氨酰胺循环。谷氨酸的回收与大脑能量代谢密切相关，是维持谷氨酸能神经传递所必需的。然而，相当数量的谷氨酸也被代谢，并作为一个代谢枢纽，连接神经元和星形胶质细胞中的葡萄糖和氨基酸代谢。谷氨酸清除的中断，导致神经元过度刺激和兴奋毒性，与几种神经退行性疾病有关。此外，脑能量稳态与谷氨酸代谢之间的联系在几种神经疾病中受到关注。在这篇综述中，我们提供了一个关于突触谷氨酸稳态的动力学和基础代谢过程的概述，重点是神经元和星形胶质细胞。特别是，我们回顾了最近发现的神经元谷氨酸摄取在突触谷氨酸稳态中的作用，并讨论了在阿尔茨海默病和亨廷顿病背景下，细胞谷氨酸代谢的当前进展。深入了解突触处依赖谷氨酸的代谢过程的精细调控，不仅将增加我们对谷氨酸稳态代谢机制的了解，还可能揭示新的代谢靶点来改善神经退行性变。
