Astrocytic–Neuronal–Astrocytic Pathway Selection for Formation and Degradation of Glutamate/GABA

Endocrinological research early recognized the importance of intercellular interactions and realized the importance of glutamatergic and GABAergic signaling. In turn this signalling depends on elaborate interactions between astrocytes and neurons, without which neurons would be unable to produce, reuse and metabolize transmitter glutamate and GABA. Details of these subjects are described in this Research Topic by key investigators in this field. It focuses on the intricate and extremely swift pathway producing these amino acid transmitters from glucose in brain but also discusses difficulties in determining expression of some of the necessary genes in astrocytes and related processes in pancreatic islets. However, it does not discuss how closely associated astrocytes and neurons are anatomically, enabling these interactions. This is elegantly shown in this cover image, kindly provided by Professor Andreas Reichenbach (University of Leipzig, Germany)

Integration between Glycolysis and Glutamate-Glutamine Cycle Flux May Explain Preferential Glycolytic Increase during Brain Activation, Requiring Glutamate

The 1988 observation by Fox et al. (1988) that brief intense brain activation increases glycolysis (pyruvate formation from glucose) much more than oxidative metabolism has been abundantly confirmed. Specifically glycolytic increase was unexpected because the amount of ATP it generates is much smaller than that formed by subsequent oxidative metabolism of pyruvate. The present article shows that preferential glycolysis can be explained by metabolic processes associated with activation of the glutamate-glutamine cycle. The flux in this cycle, which is essential for production of transmitter glutamate and GABA, equals 75% of brain glucose utilization and each turn is associated with utilization of ~1 glucose molecule. About one half of the association between cycle flux and glucose metabolism occurs during neuronal conversion of glutamine to glutamate in a process similar to the malate-aspartate shuttle (MAS) except that glutamate is supplied from glutamine, not formed from α-ketoglutarate (αKG) as during operation of conventional MAS. Regular MAS function is triggered by one oxidative process in the cytosol during glycolysis causing NAD+ reduction to NADH. Since NADH cannot cross the mitochondrial membrane (MEM) for oxidation NAD+ is re-generated by conversion of cytosolic oxaloacetate (OAA) to malate, which enters the mitochondria for oxidation and in a cyclic process regenerates cytosolic OAA. Therefore MAS as well as the “pseudo-MAS” necessary for neuronal glutamate formation can only operate together with cytosolic reduction of NAD+ to NADH. The major process causing NAD+ reduction is glycolysis which therefore also must occur during neuronal conversion of glutamine to glutamate and may energize vesicular glutamate uptake which preferentially uses glycolytically derived energy. Another major contributor to the association between glutamate-glutamine cycle and glucose utilization is the need for astrocytic pyruvate to generate glutamate. Although some oxidative metabolism occurs during glutamate formation it is only one half of that during normal tricarboxylic acid (TCA) cycle function. Glutamate’s receptor stimulation leads to potassium ion (K+) release and astrocytic uptake, preferentially fueled by glycolysis and followed by release and neuronal re-accumulation. The activation-induced preferential glycolysis diminishes with continued activation and is followed by an increased ratio between oxidative metabolism and glycolysis, reflecting oxidation of generated glutamate and accumulated lactate

Road Haulier Competition: Implications for Supply Chain Integration

Road freight competition is playing out in deregulated markets. The EU single market is a market with abundant responses in terms of haulier strategic actions. This chapter situates the crucial role of road haulier strategies in the logistics service supply chain and industrial supply chain to achieve sustainability. Competitive and sustainable transport depends on effective transport services, vehicles and transport infrastructure, and conditions that foster the development of transport and logistics services. By examining how four case firms develop competences and make use of available resources we develop insights into road haulier competition and its implications. The chapter contributes to understanding how road hauliers are part of logistics service chains as well as industrial supply chains and how the many links and relationships increase the magnitude and implications of hauliers’ performances

Brain glutamine synthesis requires neuronal aspartate: A commentary

Inspired by the paper, ‘Brain glutamine synthesis requires neuronal-born aspartate as amino donor for glial glutamate formation' by Pardo et al, a modified model of oxidation–reduction, transamination, and mitochondrial carrier reactions involved in aspartate-dependent astrocytic glutamine synthesis and oxidation is proposed. The alternative model retains the need for cytosolic aspartate for transamination of α-ketoglutarate, but the ‘missing' aspartate molecule is generated within astrocytes during subsequent glutamate oxidation. Oxaloacetate formed during glutamate formation is used during glutamate degradation, and all transmitochondrial reactions, oxidations–reductions, and cytosolic and mitochondrial transaminations are stoichiometrically balanced. The model is consistent with experimental observations made by Pardo et al

All 3 Types of Glial Cells Are Important for Memory Formation

The vertebrate brain contains neurons and 3 classical types of glia cells, astrocytes, oligodendrocytes and microglia. Astrocytes and microglia have mainly been studied in gray matter, whereas oligodendrocytes myelinate white matter tracts. Until recently microglial effects were considered mainly during pathological conditions, but is now known that microglia plays important roles also in normal brain function. All these 3 glial cell types and their collaboration with neurons are important for learning. The concept that glia cells are important for cognitive function is not new. A glial-neuronal theory of brain function was proposed by Galambos in 1961. Hyden and Egyhazi demonstrated glial RNA changes in microdissected glia cells during learning in rats in 1963, and astrocytic and oligodendrocytic involvement of K+-mediated effects of learning has been suggested and/or demonstrated from the 1960’s and onwards as recently reviewed by Hertz and Chen (Neuroscience and Biobehavioural Reviews, 2016). In 1969 van den Berg et al. showed compartmentation of glutamate in brain and thus of production of the neurotransmitters glutamate and GABA, which are essential for learning. That glutamate is synthesized in astrocytes because they in contrast to neurons express the enzyme pyruvate carboxylase was demonstrated 10-15 years later by Yu et al. in cultured astrocytes and Shank et al. in intact brain tissue. However, the present e-book focuses on more recent developments. Most information is available about astrocytic roles in learning. The importance of astrocytes in the tripartite synapse and of microglia in the tetrapartite synapse is illustrated in the front-page figure, which emphasizes the role of gliotransmitters and of Ca2+ transport through gap junctions, coupling astrocytes into a functional syncytium. Astrocytes are important for establishments of brain rhythms, which may differ in different cognitive tasks, and although the exact reason why knock-out of the astrocytic water channel AQP4 impairs memory remains to be established, several possibilities are discussed. The importance of the two astrocyte specific processes glutamate and glutamine formation and glycogenolysis is discussed in considerable detail. Glycogenolysis is important not only for astrocytic processes involved in learning, but also for those in neurons because glycolytically derived lactate has signaling functions in the extracellular space and may be accumulated in minute quantities into very specific and small neuronal structures. Some neurotransmitters stimulating glycogenolysis are also involved in psychiatric disease. Noradrenaline, released from locus coeruleus exerts direct effects on both astrocytes and neurons and in addition promotes secretion of corticotropin-releasing hormone and adrenocorticotrophic hormone (ACTH) in brain, and of glucocorticoids from the adrenal cortex, all of which are responsible for stress effects on learning. Lead causes memory impairment by inhibition of glutamine formation due to oxidative stress and reduced effectiveness of the glutathione system. The many adverse effects of fetal alcohol exposure on behaviour and learning are caused by a multitude of effects on all three types of glia cells. Traumatic brain injury also exerts multifactorial effects, including microglia/astrocyte-induced secretion of neuroinflammatory molecules and axonal disruption and oligodendrocytic dysfunction. In normal brain oligodendrocytes respond to the depolarization caused by neuronal activity with accelerated conduction velocity and increased compound action potentials which facilitate learning

Glutamine-Glutamate Cycle Flux Is Similar in Cultured Astrocytes and Brain and Both Glutamate Production and Oxidation Are Mainly Catalyzed by Aspartate Aminotransferase

The glutamine-glutamate cycle provides neurons with astrocyte-generated glutamate/γ-aminobutyric acid (GABA) and oxidizes glutamate in astrocytes, and it returns released transmitter glutamate/GABA to neurons after astrocytic uptake. This review deals primarily with the glutamate/GABA generation/oxidation, although it also shows similarity between metabolic rates in cultured astrocytes and intact brain. A key point is identification of the enzyme(s) converting astrocytic α-ketoglutarate to glutamate and vice versa. Most experiments in cultured astrocytes, including those by one of us, suggest that glutamate formation is catalyzed by aspartate aminotransferase (AAT) and its degradation by glutamate dehydrogenase (GDH). Strongly supported by results shown in Table 1 we now propose that both reactions are primarily catalyzed by AAT. This is possible because the formation occurs in the cytosol and the degradation in mitochondria and they are temporally separate. High glutamate/glutamine concentrations abolish the need for glutamate production from α-ketoglutarate and due to metabolic coupling between glutamate synthesis and oxidation these high concentrations render AAT-mediated glutamate oxidation impossible. This necessitates the use of GDH under these conditions, shown by insensitivity of the oxidation to the transamination inhibitor aminooxyacetic acid (AOAA). Experiments using lower glutamate/glutamine concentration show inhibition of glutamate oxidation by AOAA, consistent with the coupled transamination reactions described here