3.2 Glial–Neuronal Shuttle Systems

The glutamine–glutamate cycle between astrocytes and neurons is an essential part of neuronal function and activity. However, this cycle is not stoichiometric and is modulated by different regulatory mechanisms. By this means, in particular, the astrocytes are flexible in their intracellular regulation of metabolism and their ability to support the neurons in form of energy substrates and precursors for the neurotransmitter glutamate. Among conventional biochemical and molecular studies, ex vivo and in vitro C‐NMR spectroscopy has been used to monitor neural function, tissue metabolism, and neuronal–glial metabolic interactions. Special emphasis has been given to the metabolic specialization of astrocytes and its enzymatic regulation. For this purpose primary cell cultures are useful tools to study neuronal–glial metabolic relationships as the extracellular fluid can be investigated and manipulated by various stimuli. In cultured astrocytes, glucose is utilized predominantly anaerobically. Glycolysis is interrelated to the astrocytic tricarboxylic acid (TCA) cycle via bidirectional signals and metabolic exchange processes between astrocytes and neurons. Besides glucose oxidation, neuronally released glutamate is metabolized through the glial TCA cycle, while astrocyte‐derived glutamine is used by the neurons as an energy substrate and glutamate precursor. The flexibility of glutamate‐ and glutamine metabolism depends on ammonia‐ and energy homeostasis, and the pyruvate recycling pathway in astrocytes modulates the glutamine–glutamate cycle. C‐NMR studies have further extended the concept of the “nonstoichiometric” glutamate–glutamine cycle between neurons and astrocytes by the alanine/lactate as well as leucine/a‐ketoisocaproate (a‐KIC) shuttles between neurons and astrocytes. These shuttles contribute to nitrogen transfer from neurons to astrocytes and recycling of energy substrates for neurons, thereby promoting intercellular glutamine– glutamate cycling. The provision of neuronal energy substrates is further regulated by intracytosolic pyruvate compartmentation in astrocytes. In essence, the metabolic flexibility and compartmentalized enzymatic specialization of astrocytes buffers the brain tissue against metabolic impairments and excitotoxicity in response to extracellular stimuli. The knowledge about these mechanisms is important for the understanding of the physiological and pathophysiological regulation of neural metabolism and general brain function. List of Abbreviations: ALAT, alanine aminotransferase; BBB, blood–brain barrier; BCAA, branched‐chain amino acid; cME, cytoplasmic malic enzyme; GABA, g‐aminobutyric acid; GDH, glutamate dehydrogenase; GS, glutamine synthetase; HE, hepatic encephalopathy; a‐KIC, a‐ketoisocaproate; LDH, lactate dehydrogenase; ME, malic enzyme; mME, mitochondrial malic enzyme; MSO, methionine–sulfoximine; PAG, phosphate‐activated glutaminase; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; 3‐NPA, 3‐nitropropionic acid; PEPCK, phosphoenolpyruvate carboxykinase; PK, pyruvate kinase; PEP, phosphoenolpyruvate; TBOA, D,L‐threo‐b‐benzyloxyaspartate; TCA, tricarboxylic acid cycle