Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.

Physiology of astroglia

Neurons are metabolically handicapped in the sense that they are not able to perform de novo synthesis of neurotransmitter glutamate and γ-aminobutyric acid (GABA) from glucose. A metabolite shuttle known as the glutamate/GABA-glutamine cycle describes the release of neurotransmitter glutamate or GABA from neurons and subsequent uptake into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as neurotransmitter precursor. In this review, the basic properties of the glutamate/GABA-glutamine cycle will be discussed, including aspects of transport and metabolism. Discussions of stoichiometry, the relative role of glutamate vs. GABA and pathological conditions affecting the glutamate/GABA-glutamine cycling are presented. Furthermore, a section is devoted to the accompanying ammonia homeostasis of the glutamate/GABA-glutamine cycle, examining the possible means of intercellular transfer of ammonia produced in neurons (when glutamine is deamidated to glutamate) and utilized in astrocytes (for amidation of glutamate) when the glutamate/GABA-glutamine cycle is operating. A main objective of this review is to endorse the view that the glutamate/GABA-glutamine cycle must be seen as a bi-directional transfer of not only carbon units but also nitrogen units.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2006.03913.x

The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer.

Metabolism and role of glutamate in mammalian brain.

Astrocytic energy demand is stimulated by K(+) and glutamate uptake, signaling processes, responses to neurotransmitters, Ca(2+) fluxes, and filopodial motility. Astrocytes derive energy from glycolytic and oxidative pathways, but respiration, with its high-energy yield, provides most adenosine 5' triphosphate (ATP). The proportion of cortical oxidative metabolism attributed to astrocytes ( approximately 30%) in in vivo nuclear magnetic resonance (NMR) spectroscopic and autoradiographic studies corresponds to their volume fraction, indicating similar oxidation rates in astrocytes and neurons. Astrocyte-selective expression of pyruvate carboxylase (PC) enables synthesis of glutamate from glucose, accounting for two-thirds of astrocytic glucose degradation via combined pyruvate carboxylation and dehydrogenation. Together, glutamate synthesis and oxidation, including neurotransmitter turnover, generate almost as much energy as direct glucose oxidation. Glycolysis and glycogenolysis are essential for astrocytic responses to increasing energy demand because astrocytic filopodial and lamellipodial extensions, which account for 80% of their surface area, are too narrow to accommodate mitochondria; these processes depend on glycolysis, glycogenolysis, and probably diffusion of ATP and phosphocreatine formed via mitochondrial metabolism to satisfy their energy demands. High glycogen turnover in astrocytic processes may stimulate glucose demand and lactate production because less ATP is generated when glucose is metabolized via glycogen, thereby contributing to the decreased oxygen to glucose utilization ratio during brain activation. Generated lactate can spread from activated astrocytes via low-affinity monocarboxylate transporters and gap junctions, but its subsequent fate is unknown. Astrocytic metabolic compartmentation arises from their complex ultrastructure; astrocytes have high oxidative rates plus dependence on glycolysis and glycogenolysis, and their energetics is underestimated if based solely on glutamate cycling.

https://journals.sagepub.com/doi/pdf/10.1038/sj.jcbfm.9600343

Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis.

γ-Aminobutyrate (GABA) is a major inhibitory neurotransmitter in the adult mammalian brain. GABA is also considered to be a multifunctional molecule that has different situational functions in the central nervous system, the peripheral nervous system, and in some nonneuronal tissues. GABA is synthesized primarily from glutamate by glutamate decarboxylase (GAD), but alternative pathways may be important under certain situations. Two types of GAD appear to have significant physiological roles. GABA functions appear to be triggered by binding of GABA to its ionotropic receptors, GABAAand GABAC, which are ligand-gated chloride channels, and its metabotropic receptor, GABAB. The physiological, pharmacological, and molecular characteristics of GABAA receptors are well documented, and diversity in the pharmacologic properties of the receptor subtypes is important clinically. In addition to its role in neural development, GABA appears to be involved in a wide variety of physiological functions in tissues and organs outside the brain.

Richard P. Shank

Papers

Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools.