The Glutamate-Glutamine (GABA) Cycle: Importance of Late Postnatal Development and Potential Reciprocal Interactions between Biosynthesis and Degradation.
The Glutamate-Glutamine (GABA) Cycle: Importance of Late Postnatal Development and Potential Reciprocal Interactions between Biosynthesis and Degradation.
复制标题
DOI：
10.3389/fendo.2013.00059
复制
发表时间：
2013
影响因子：
5.2
通讯作者：
Hertz L
中科院分区：
文献类型：
--
作者：
Hertz L
研究谷氨酸-谷氨酰胺（GABA）循环及其与葡萄糖中谷氨酸和GABA的脑生物合成及其随后的代谢的联系的金标准是通过13C磁共振波谱（NMR）进行的优雅的体内研究，显示了循环中的大通量。然而，在完整脑组织（如免疫组织化学）、脑切片、培养的脑细胞和线粒体中进行的更简单的实验也为理解谷氨酸/GABA生物合成和降解的细节、机制和功能后果做出了重要贡献。本综述的目的是试图整合来自不同来源的证据，包括：(1)α-酮戊二酸最初转化为谷氨酸的酶；（ii）特别是谷氨酸氧化基本上局限于星形胶质细胞的可能性；（iii）个体发育上谷氨酰胺-谷氨酸（GABA）循环功能的迟发和成熟。基于天冬氨酸对谷氨酸合成的功能重要性的途径模型表明，谷氨酸和GABA的生物合成和降解可能存在相互作用的途径，谷氨酸氧化起始的默认机制是转氨化。发育成熟的晚与脑皮层胶质细胞形成的晚有关，脑皮层功能由单纯的神经元向神经元-星形细胞转变。这种转换与能源需求和生产的巨大增加有关，并讨论了潜在产生的功能增益的特征。这些可能包括学习机制的改变，在小鼠中，新生动物缺乏气味学习与厌恶刺激的配对，但这种关联在10-12天后发展起来。这种可能性表明，类似的成熟变化可能会导致新生儿大脑和后期发育过程中学习方式的差异。
The gold standard for studies of glutamate–glutamine (GABA) cycling and its connections to brain biosynthesis from glucose of glutamate and GABA and their subsequent metabolism are the elegant in vivo studies by 13C magnetic resonance spectroscopy (NMR), showing the large fluxes in the cycle. However, simpler experiments in intact brain tissue (e.g., immunohistochemistry), brain slices, cultured brain cells, and mitochondria have also made important contributions to the understanding of details, mechanisms, and functional consequences of glutamate/GABA biosynthesis and degradation. The purpose of this review is to attempt to integrate evidence from different sources regarding (i) the enzyme(s) responsible for the initial conversion of α-ketoglutarate to glutamate; (ii) the possibility that especially glutamate oxidation is essentially confined to astrocytes; and (iii) the ontogenetically very late onset and maturation of glutamine–glutamate (GABA) cycle function. Pathway models based on the functional importance of aspartate for glutamate synthesis suggest the possibility of interacting pathways for biosynthesis and degradation of glutamate and GABA and the use of transamination as the default mechanism for initiation of glutamate oxidation. The late development and maturation are related to the late cortical gliogenesis and convert brain cortical function from being purely neuronal to becoming neuronal-astrocytic. This conversion is associated with huge increases in energy demand and production, and the character of potentially incurred gains of function are discussed. These may include alterations in learning mechanisms, in mice indicated by lack of pairing of odor learning with aversive stimuli in newborn animals but the development of such an association 10–12 days later. The possibility is suggested that analogous maturational changes may contribute to differences in the way learning is accomplished in the newborn human brain and during later development.