Medical Gas Research

: 2019  |  Volume : 9  |  Issue : 1  |  Page : 24--45

Neurointegrity and neurophysiology: astrocyte, glutamate, and carbon monoxide interactions

Vicki L Mahan 
 Division of Pediatric Cardiothoracic Surgery in the Department of Surgery, St. Christopher's Hospital for Children/Drexel University College of Medicine, Philadelphia, PA, USA

Correspondence Address:
Vicki L Mahan
Division of Pediatric Cardiothoracic Surgery in the Department of Surgery, St. Christopher«SQ»s Hospital for Children/Drexel University College of Medicine, Philadelphia, PA


Astrocyte contributions to brain function and prevention of neuropathologies are as extensive as that of neurons. Astroglial regulation of glutamate, a primary neurotransmitter, is through uptake, release through vesicular and non-vesicular pathways, and catabolism to intermediates. Homeostasis by astrocytes is considered to be of primary importance in determining normal central nervous system health and central nervous system physiology - glutamate is central to dynamic physiologic changes and central nervous system stability. Gasotransmitters may affect diverse glutamate interactions positively or negatively. The effect of carbon monoxide, an intrinsic central nervous system gasotransmitter, in the complex astrocyte homeostasis of glutamate may offer insights to normal brain development, protection, and its use as a neuromodulator and neurotherapeutic. In this article, we will review the effects of carbon monoxide on astrocyte homeostasis of glutamate.

How to cite this article:
Mahan VL. Neurointegrity and neurophysiology: astrocyte, glutamate, and carbon monoxide interactions.Med Gas Res 2019;9:24-45

How to cite this URL:
Mahan VL. Neurointegrity and neurophysiology: astrocyte, glutamate, and carbon monoxide interactions. Med Gas Res [serial online] 2019 [cited 2020 Feb 17 ];9:24-45
Available from:

Full Text


Central nervous system (CNS) progenitor cells differentiate into three main cell types - neurons, astrocytes, and oligodendrocytes. Cell proliferation, survival, migration, differentiation, and apoptosis are regulated by multiple signals including neurotransmitters that are critical for normal brain development and function. [1],[2],[3],[4],[5],[6],[7] Composed of electrically excitable neuronal networks that are connected by chemical synapses, CNS homeostasis is primarily provided by the non-externally excitable astrocytes. The latter, identified by an algorithm based on cytological features, [8] supplies neurons with glutamate, the conjugate base of glutamic acid and the major neurotransmitter of the CNS. Astroglial regulation of the neurotransmitter is through uptake, release through vesicular and non-vesicular pathways, and catabolism to intermediates [9],[10],[11],[12],[13],[14],[15],[16] and requires that glutamate is adequately and constantly replenished and that anaplerosis and cataplerosis are balanced. [17],[18],[19],[20],[21],[22],[23],[24] Directed to several different biochemical pathways, glutamate is important to glutamate-glutamine cycling. Net formation of glutamate from glucose is required for glutamatergic neuronal signaling in the CNS, requires astrocytic pyruvate carboxylase (PC) and astrocytic tricarboxylic acid (TCA) cycle activity and is required for CNS function. Return of glutamate to neurons and continued release of glutamate depend on astrocyte glutamine synthetase (GS) activity. The dynamic metabolic fluxes in astrocytes and cellular localization of metabolic processes determine metabolic formation and degradation of glutamate.

Astrocyte contributions to brain function and prevention of neuropathologies are as extensive as that of neurons. Homeostasis of glutamate by astrocytes is considered to be of primary importance in determining normal CNS health and physiology. [25],[26],[27],[28],[29],[30],[31][32] A major metabolite connecting glucose and amino acid metabolism via the tricarboxylic acid cycle, glutamate is an immediate precursor of γ-aminobutyric acid (GABA), initially excitatory and later inhibitory, and is required for normal development of the brain. It acts as a trophic factor that influences proliferation, migration, differentiation, synapse maturation, and cell death during CNS development. [33],[34] Excitation by GABA is a result of high intracellular concentrations of chloride and is followed by sequential formation of GABA-releasing and glutamatergic synapses. Giant depolarizing potentials, generated in part by excitatory actions of GABA, result in the generation of large oscillations of intracellular calcium and activity-dependent synapse formation (glutamate and GABA synapses) and neuronal growth. A chloride-extruding system develops later and results in the inhibitory effects of GABA. [35],[36],[37],[38] GABA is, thus, inhibitory in the developed human brain, glutamate excitatory, and GABA is required for glutamate synapse development in the CNS.

The physiologic changes noted above depend on the biochemical requirements of the developing brain for normal functioning. These constantly change and evolve in all age groups. While the TCA cycle is important for glutamate synthesis in both the astrocyte and the neuron, the shuttle of glutamate from neurons to astrocytes is limited in the neonatal brain. This is compensated for by astrocytic anaplerosis via increased pyruvate carboxylation. [20],[24],[39] Fewer astrocytes are present in the newborn brain compared to the adult brain and PC activity is lower. Gliogenesis occurs mainly during the first few weeks after birth. Glutamate levels double from week 32 gestational age and continue to increase in the first year of life. [40] The major role of neurotransmitters, including glutamate, in neuronal differentiation, migration, and survival in the developing brain is mainly through facilitating the entry of Ca 2+ [41],[42] and the astroglial cradle (formed by perisynaptic processes) that is necessary for synaptogenesis, maturation, isolation, and maintenance of synapses and is dependent on the homeostasis of glutamate. Synaptic connectivity, synaptic plasticity, and information processing of the CNS proceeds only with an intact and working system. [43],[44],[45] Astrogenesis is required for the majority of functional synapses - morphologic and functional diversity occurs during development. [46],[47] Glutamate is central to these dynamic changes and resulting clinical outcomes - gasotransmitters may affect these diverse interactions positively or negatively. The effect of carbon monoxide, an intrinsic CNS gasotransmitter, in the complex astrocyte homeostasis of glutamate may offer insights to normal brain development, protection, and its use as a neuromodulator and neurotherapeutic. In this article, we will review the effects of carbon monoxide on astrocyte homeostasis of glutamate.

 Metabolism of Glutamate In The Astrocyte And Neuron

Glutamate functions as a neurotransmitter, as a precursor of neuronal neurotransmitters, as an energy substrate and buffer, and as a nitrogen buffer. Most CNS glutamate is produced within the brain as the blood-brain-barrier effectively excludes most of the blood-borne glutamate and there is net removal of glutamine. The neurotransmitter is not uniformly distributed and, potentially neurotoxic, low extracellular fluid concentrations of glutamate are necessary to avoid excitotoxity. The required levels for normal function vary in different regions of the brain and during different times of life. Concentration influences its dual role as neurotransmitter and energy source. A concentration gradient of CNS glutamate, vesicles > cytosol/mitochondria > extracellular fluid, is a result of the effectiveness of astrocyte glutamate synthesis, glutamate catabolism, and glutamate transporters. De novo synthesis of TCA cycle intermediates from glucose catalyzed by PC results in the formation of oxaloacetate, essential for the de novo synthesis of glutamate and the glutamine that is transferred from astrocytes to neurons to maintain the pool of glutamate. Complete and/or partial pyruvate recycling via oxidation of glutamate is important in balancing the PC anapleurotic reaction. These processes are dynamic and change with brain activity and the release of K + by synaptic terminals during depolarization. [39],[48] Metabolism of glutamate is affected via the GS reaction, glutamate/α-ketoglutarate-linked aminotransferases coupled to the glutamate dehydrogenase (GDH) reaction, decarboxylation to GABA, and glutathione (GSH).

Glutamine synthetase reaction

The glutamate-glutamine cycle [Figure 1] describes the transfer of glutamate from neurons to astrocytes and subsequent return of glutamine from astrocytes to neurons. There is not a stoichiometric relationship between glutamate flux out of the presynaptic neurons and the flux of glutamine from astrocytes back to the presynaptic terminals. Important to the process, astrocytes represent a heterogenous population of cells and GS, an astrocyte marker. [49] Three types of GS have been identified, GSI, GSII, and GSIII. Humans have the GSII type. [50] Located primarily in the cytoplasm of astrocytes, human GS is important for removal of ammonia (NH 3 ) and is a major route for removal of glutamate from the CNS.{Figure 1}

Net synthesis of the non-toxic glutamine, precursor of glutamate and GABA, occurs only in astrocytes and requires cellular compartmentalization of GS and PC. [22] Catalyzed by GS, L-glutamate combines with ammonia and adenosine triphosphatase (ATP) to form L-glutamine, adenosine diphosphate (ADP), and phosphate:

L-Glutamate + NH 3 + ATP ↔ L-Glutamine + ADP + Pi.

Glutamine is a major source of CNS glutamate via the glutaminase (present in neurons and astrocytes) reaction [51] :

L-Glutamine + H 2 O → L-Glutamate + NH 3 .

The glutamate-glutamine cycle loses intermediates to other pathways and de novo synthesis of glutamine in astrocytes is needed to continue its operation. Anaplerosis is mediated by PC and ranges from 6 to 35% of the rate of the TCA cycle which meets this requirement [52] with the resulting oxaloacetate entering the Krebs cycle:

Pyruvate + CO 2 + ATP → Oxaloacetate + ADP + Pi.

Glutamate/α-ketoglutarate-linked aminotransferases coupled to the glutamate dehydrogenase reaction

Catabolism of glutamate to carbon dioxide (CO 2 ) requires access to the TCA cycle and pyruvate recycling. The coupling of an aminotransferase reaction to the GDH reaction generates ammonia or incorporates ammonia into an amino acid. The TCA cycle-derived α-ketoglutarate provides the carbon-skeleton for glutamate and maintains glutamate nitrogen levels.

The glutamate-glutamine cycle is coupled to the α-ketoglutarate cycle via the mitochondrial GDH:

L-Glutamate + NAD(P) + + H 2 O ↔ α-Ketoglutarate + NH 4 + + NAD(P)H.

Present as two isoforms in humans (GDH1 and GDH2), the enzymes differ greatly with regards to allosteric regulation. [53] GDH is the major route of glutamate oxidation in astrocytes. [26]

As a co-substrate in all aminotransferase catalyzed reactions, glutamate also has a major role in astrocyte amino-acid interconversion. α-Ketoglutarate-linked aminotransferases are important for the transport of reducing equivalents from cytosol to mitochondria. Three aminotransferases are important players in the conversion of glutamate to α-ketoglutarate - the aspartate, alanine, and branched chain amino acid aminotransferases. The first is the major enzyme responsible for production of α-ketoglutarate that can be oxidatively metabolized in the TCA cycle to form oxaloacetate and then aspartate.

Mitochondrial aspartate aminotransferase (AAT) catalyzes the following reaction:

L-Glutamate + Oxaloacetate ↔ L-Aspartate + α-Ketoglutarate.

The reaction proceeds readily in both directions and is important in the TCA cycle. AAT, present in all tissues, has the highest specific activity in the brain.

Located in the cytoplasm and requiring the cofactor pyridoxal-5-phosphate, alanine aminotransferase catalyzes the interconversion of alanine, α-ketoglutarate, pyruvate, and glutamate. In the neuron,

L-Glutamate + Pyruvate → L-Alanine + α-Ketoglutarate.

In the astrocyte,

L-Alanine + α-Ketoglutarate → L-Glutamate + Pyruvate.

This nitrogen shuttle requires uptake of alanine by astrocytes and transamination of alanine in the astrocytes. [54]

The essential branched chain amino acids valine, leucine, and isoleucine rapidly cross the blood-brain barrier and are taken up by astrocytes. CNS uptake requires that an equivalent amount of nitrogen exits the brain to maintain nitrogen homeostasis. Intracellular amino acid nitrogen is incorporated into glutamine which then moves to the extracellular compartment. In astrocytes, the mitochondrial isozyme of the branched chain amino acid aminotransferase isozymes catalyzes the metabolism of valine, leucine and isoleucine by transamination with α-ketoglutarate to form α-ketoisovalerate, α-ketoisocaproate, and α-keto-β-methylvalerate, respectively:

L-Valine + α-Ketoglutarate ↔ L-Glutamate + α-Ketoisovalerate

L-Leucine + α-Ketoglutarate ↔ L-Glutamate + α-Isocaproate

L-Isoleucine + α-Ketoglutarate ↔ L-Glutamate + α-Keto-β-methylvalerate.

The 3 branched chain amino acids are sources of glutamate in the astrocyte. [26],[55],[56],[57],[58]

Decarboxylation to γ-aminobutyric acid

Decarboxylation of glutamate by glutamic acid decarboxylase (GAD) results in the inhibitory neurotransmitter GABA [Figure 1]. Two isozymes, GAD65 and GAD67, are restricted to neurons and primarily GABAergic neurons and catalyze the reaction:

L-Glutamate → GABA + CO 2 .

GABA is released by the neuron and taken up by astrocytes. Metabolism of GABA in the astrocyte to the TCA cycle intermediate succinate is catalyzed by GABA-transaminase and succinic semialdehyde dehydrogenase, the GABA shunt:

GABA + α-Ketoglutarate ↔ Succinic Semialdehyde + L-Glutamate

Succinic Semialdehyde + NAD + → Succinate + NADH.

Glutamate is a product of the first reaction.


GSH is a major water soluble antioxidant of the brain, is a major source of peptide-bound glutamate and is more prevalent in astrocytes than in neurons. Uptake of cysteine is the major determinant of its production in the CNS and is mediated by the excitatory amino acid transporter 3 and the alanine, serine and cysteine system that transports alanine, serine, and cysteine. [59] Synthesis requires 2 ATP-dependent steps, the first catalyzed by γ-glutamylcysteine ligase (rate limiting step) and the second by glutathione synthetase:

L-Glutamate + L-Cysteine + ATP → L-γ-Glutamylcysteine + ADP + Pi

L-γ-Glutamylcysteine + Glycine + ATP → GSH + ADP + Pi.

Astrocytic GSH released to the interstitial space is hydrolyzed to γ-glutamycysteine and glycine. γ-glutamycysteine is then hydrolyzed to glutamate and cysteine that are then actively transported into neurons by excitatory amino acid transporter 3 and excitatory amino acid transporter 2.

Other sources of astrocyte glutamate

5-Oxoproline (5-OP), pyroglutamic acid, is ubiquitous in nature and is the cyclic lactam of glutamate, a reservoir of glutamate. It is found as a free metabolite in living cells and as an N-terminal modification in antibodies, enzymes, structural proteins, neuronal peptides and hormones (including the accumulating peptides in Alzheimer's disease and familial dementia). The γ-glutamyl cycle describes the enzymatic formation of 5-OP from glutathione by γ-glutamyl cyclotransferase and degradation of 5-OP to L-glutamate by 5-oxoprolinase. 5-Oxoprolinase, a pyro-glutamic acid-cleaving enzyme, acts on 5-OP to form L-glutamate [60],[61] :

5-OP + ATP + 2H 2 O → L-glutamate + ADP + Pi.

 Physiology of Glutamate In The Central Nervous System

Glutamate is the major neurotransmitter in the CNS and mediates the fast excitatory signaling needed for motor/sensory/autonomic processing, is an energy substrate, and is important for neurometabolic and neurovascular coupling. Astrocytes sense local glutamate activity and respond to this by elevations in the intracellular Ca 2+ concentration. Also capable of releasing glutamate, proposed mechanisms of release include hemichannels, anion channels, and exocytosis. [62],[63],[64],[65],[66],[67],[68] Functional integrity of astrocytes and neurons is necessary for transfer and processing of information determined by glutamate release and concentrations. Involvement of glutamate in the pathogenesis of CNS diseases due to excessive release, reduced uptake, and/or alteration of receptor function has been postulated. [69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80]

Critical to maintaining CNS integrity and preventing neuropathology, glutamate homeostasis is an important function of astrocytes. Initially considered to be "glue" keeping the nerve cell elements together and involved in various housekeeping functions, astrocyte function in the tripartite synapse (synapse between a pre- and post-synaptic neuron with bidirectional communication with one astrocyte) emphasizes astrocyte participation in synaptic signaling. This is done through exchanging information with the pre- and postsynaptic neurons, responding to synaptic activity, and regulating synaptic activity. [81],[82],[83],[84],[85] Energy substrates and transmitter precursors are provided and waste products are removed. Close proximity to large numbers of neurons enables single astrocytes to promote synchrony of neuronal action potential firing resulting from glutamate release. [86],[87],[88],[89] Adaptive to their environment, astrocytes are able to change the expression of large numbers of proteins affecting CNS function. Heterogeneity in astrocyte receptor expression, gap junction coupling, membrane currents and morphology occur between and within brain regions responding to and resulting in dynamic physiology. [90],[91],[92],[93],[94] Interplay between neuronal signaling to astrocytes and astrocytic signaling to neurons involve ATP and glutamate which coordinately activate astrocytes through mobilization of their internal Ca 2+ . This triggers release of neuroactive molecules including ATP and glutamate from astrocytes. Ca 2+ waves are generated in astrocytes and neuronal synaptic transmission and neuronal excitability are modulated. [95]

Presynaptic factors (release probability, quantal content, vesicle composition), modulation of the concentration and longevity of glutamate in the extracellular space (diffusion, actions of glutamate transporters), and postsynaptic factors (types and locations of ionotropic glutamate receptors, their numbers, and nature and locations of associated intracellular signaling systems) modulate excitation at glutamatergic synapses. Molecular components include synthesis and release of glutamate, glutamate-gated ion channel receptors (iGluRs), glutamate G-protein-coupled receptors (GPCRs), and glutamate transporters. Membrane receptors for most major neurotransmitters and neuromodulators are expressed by astrocytes and are important for neural communication, memory formation, learning, and regulation. Neurotransmitter receptors form ion channels to mediate rapid membrane potential changes, exert their action through slower intracellular signaling pathways, and serve as synaptic scaffolds to regulate synapse formation and maintenance (non-ionotropic function). These receptors usually are not specific for glutamate and receptors (classified based on mammalian pharmacology and identified as being ionotropic or metabotropic, responsible for the glutamate-mediated postsynaptic excitation of neural cells, and functions include modulation of synaptic plasticity) result when sixteen functional subunits assemble in tetrameric complexes to form GluR1-GluR4 for α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors(occur in 2 alternatively spliced versions, flip and flop), GluR5-GluR7 and KA1-KA2 for kainate receptors, and GluN1, GluN2A-GluN2D, and GluN3A-B for N-methyl-D-aspartate (NMDA) receptors. [90] AMPA receptors, kainate receptors, and NMDA receptors are ionotropic glutamate receptors in humans. Metabotropic glutamate receptors (mGluRs), GPCRs that bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling receptors, are classified into three groups based on their sequence homology, pharmacological profile, and coupling to intracellular transduction pathways - Group I mGLuRs consist of mGlu1, mGlu5, and their splice variants; Group II includes mGlu2 and mGlu3; and Group III mGlu4, mGlu6, mGlu7, mGlu8, and some splice variants. [91],[92] While functional heterogeneity of these components between astrocytes within and across brain regions exists, impact on physiological and clinical presentations remains undefined. [93],[94],[96],[97],[98],[99],[100]

The intracellular signaling cascades depend on astroglial activation occurring within milliseconds to neuronal activity and neurotransmitters released at synapses. Fast responses occur as changes in intracellular free Ca 2+ concentration occur. [101],[102],[103] Neurotransmitters released from neurons are thought to activate receptors at the astroglial membrane inducing activation of phospholipase C and the concomitant production of IP3 which triggers release of endoplasmatic reticulum Ca 2+ . [104],[105] Hemichannels open and other Ca 2+ dependent neurotransmitter release mechanisms are activated. Hemichannel opening allows release of glutamate into the extracellular space which can activate purinergic or NMDA receptor channels in astrocytes and induce changes in free Ca 2+ concentration. [106],[107] Low glutamate concentrations result in short-acting Ca 2+ oscillations in single astrocytes. Higher concentrations result in astrocyte-to-astrocyte propagating Ca 2+ waves. [108] Different neurotransmitters result in different Ca 2+ responses in astrocytes and may be able to activate entire astroglial networks. [109] Because astrocytes envelope synapses, release of glutamate also activates neighboring pre- and post-synaptic neurons and, therefore, modulate surrounding synaptic activity. [110],[111]

Synthesis and release of glutamate

Glutamate has to be present in the right concentration, in the right place, and for the right amount of time to regulate brain development, cellular survival, differentiation, glutamate elimination, and formation and elimination of synapses. There are no special or unique synthetic or degradative enzymes for L-glutamate - the amino acid is synthesized from α-ketoglutarate and glutamine. Loss of glutamine may result, but its replenishment is ensured by other biochemical pathways noted above.

Spontaneous release of glutamate from astrocytes helps to set the basal probability of neurotransmitter release via metabotropic glutamate receptor activation. [112] K 2P channels in astrocytes (isoforms TWIK1, TREK1, TREK2, TASK1, and TASK3) are also critical for glutamate release. [113],[114],[115] In astrocytes that are part of a tripartite synapse, calcium oscillations cause proximal and distal release of glutamate to surrounding neurons. [116] After release of glutamate from neurons, transport of glutamate to astrocytes, conversion of glutamate to glutamine in astrocytes, transport of glutamine from astrocytes to neurons and reconversion of glutamine to glutamate in neurons completes the glutamate/glutamine cycle. Astrocytic regulation ensures that greater than 60% of synaptic glutamate is processed by the associated astrocyte. Swelling and shrinking of astrocytes may allow reduction of leakage and/or prevent spillover of glutamate.

Glutamate-gated ion channels

iGluRs, integral membrane proteins, are important to CNS synaptogenesis, neuronal pathfinding, neuronal viability, and regulation of synaptic efficacy. [117] These are ligand-gated nonselective cation channels that result in flow of K + , Na + , and Ca 2+ with glutamate binding. Excitatory postsynaptic current results and is depolarizing. Excitatory synaptic transmission in the human brain depends on a high concentration of glutamate at the postsynaptic membrane after its release from presynaptic terminals. iGluRs are the major mediators of excitation and activation of AMPA receptors, NMDA receptors, and/or kainate receptors and require proximity of the amino acid. Ion channel pores formed by these receptors activate with binding of glutamate. Overstimulation results in neurodegeneration and neuronal damage due to excitotoxicity. Synaptic plasticity and molecular mechanisms of learning and memory are also dependent on iGluRs.

Major neurological and neurodevelopmental disease processes are associated with iGluR mutations, misexpression, misregulation, or deficits in signaling. [118],[119],[120],[121],[122],[123],[124],[125] Encoded by 18 genes which coassemble to form 3 major families (AMPA, NMDA, and kainate), these receptors form tetrameric ligand-gated channel pores that allow influx of Na + and Ca 2+ . AMPA iGluR subunits include GluA1, GluA2, GluA3, and GluA4, NMDA subunits GluN1, Glun2A, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3B, and kainate subunits GluK1, GluK2, GluK3, GluK4, and GluK5. A fourth family is formed by the delta subunits GluD1 (GluRδ1) and GluD2 (GluRδ2). In the brain, GluA1/GluA2 (AMPA receptor subtype), GluN1/GluN2A/GluN2B (NMDA receptor subtype) and GluK2/GluK5 (kainate receptor subtype) are the most widely expressed. Composed of 4 large subunits, iGluRs contain 4 discrete semiautonomous domains - the extracellular amino-terminal domain, the extracellular ligand-binding domain, the TMD - harbors the ion channel, and an intracellular C-terminal domain. Binding of glutamate to the extracellur ligand-binding domain allows the influx of ions and generation of synaptic current in the brain. Various ionotropic glutamate receptors on postsynaptic cells determine potentiation or depression of the cell. Glutamate, acting on glutamate receptors, causes Ca 2+ to influx into the postsynaptic cell resulting in a cascade of cell processes that can result in damage to cell structures, and, possibly, cell death. Clinical neuropathology associated with glutamate excitotoxicity include traumatic brain injury, cerebral ischemia, hyperalgesia, attention deficit hyperactivity disorder, autism, Huntington's disease, multiple sclerosis, Parkinson's disease, Rasmussen's encephalitis, schizophrenia, seizures and, possibly, acquired immune deficiency syndrome dementia complex, Alzheimer's disease, amyotrophic lateral sclerosis, combined systems disease (vitamin B12 deficiency), depression, anxiety, drug addiction/tolerance/dependency, glaucoma, hepatic encephalopathy, hydroxybutyric aminoaciduria, hyperhomocysteinemia, homocysteinuria, hyperprolinemia, lead encephalopathy, Leber's disease, mitochondrial encephalopathy, lactic-acidosis, and stroke-like episodes syndrome, myoclonic epilepsy with ragged-rebfibers, mitochondrial abnormalities, neuropathic pain syndromes, nonketototic hyperglycinemia, olivopotocerebellar atrophy, essential tremor, Rett syndrome, sulfite oxidase deficiency, Wernicke's encephalopathy, and depersonalization disorder.

α-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors

Widely expressed in the adult brain, AMPA receptors are the first iGLuRs to appear during CNS development. [126],[127],[128] Most excitatory synaptic transmission in the CNS is mediated by glutamate through activation of AMPA receptors. Interaction of postsynaptic proteins with AMPA receptor subunits control AMPA receptor insertion, location, pharmacology, synaptic transmission, and neuroplasticity. [129] Altering the number of AMPA receptors is the basis of synaptic neuroplasticy - synapses become stronger with the addition of AMPA receptors. [130],[131] Subunit composition varies depending on the brain region and the functional properties of AMPA receptors and their trafficking depend on subunit composition. [132],[133] The majority of AMPA receptors in the CNS contain GluA2 which is important for changing Ca 2+ permeability and resulting synaptic transmission and intracellular signaling. [134] AMPA receptor Ca 2+ permeability depends on the GluA2 subunit mRNA and mediates fast excitatory synaptic transmission in the CNS. Incorporation of the GluA2 subunit reduces the Ca 2+ permeability and channel conductance and prolongs the decay kinetics of a synaptic current. [135] A switch in AMPA receptor phenotype during physiological functioning and under pathological conditions results in a change in information processing and Ca 2+ -dependent signaling at synapses. [136]

N-methyl-D-aspartate receptors

Astrocyte AMPA receptors and NMDA receptors differ in their sensitivity to glutamate as well as their desensitization rate and provide information about the concentration and duration of glutamate in the synaptic cleft. The latter form glutamate-gated ion channels that are highly permeable to Ca 2+ (main source of calcium responsible for glutamate-induced excitotoxicity), relay physiological signals into neurons, and trigger intracellular signaling cascades that can lead to cell death. [16] NMDA receptor activation resulting in increased Ca 2+ concentrations triggers synaptic plasticity and amount and kinetics of the calcium influx determine physiology. [137] Essential but potentially harmful, subunit composition of NMDA receptors determines functionally distinct CNS properties. [138],[139] Seven subunits have been identified - GluN1 (8 isoforms), GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3b - and are brain region-specific. All of the subunits have 4 domains, the N-terminal domain, the agonist binding domain, the TMD, and the intracellular C-terminal domain. N-terminal domain, agonist binding domain, and TMD are targeted by endogenous or synthetic allosteric modulators. [140]

Ongoing modification of subunit composition with resultant changes in biochemical interactions and physiology continues throughout life. Composition of their heterotetrameric assembly, usually two GluN1 and two GluN2 subunits, determines function of the NMDA receptors. GluN1 and GluN2-containing NMDA receptor complexes are abundant throughout the CNS. GluN2 subunits define channel properties and subcellular localization of the receptor. Diheteromeric (GluN1/GluN3) or triheteromeric (GluN1/GluN2/GluN3) complexes are formed if GluN3 subunits are incorporated. [140] Combinations of subunit assembly results in functionally different NMDA receptors and physiologic differences in the CNS. Although GluN1 is ubiquitously expressed in the CNS, developmental and regional variations depend on the type of GluN1 isoform. [140] GluN2A-D, forming glutamate-gated ion channels that are heterogeneous and widely permeable to calcium ions, result in normal neurophysiology as well as neuropathology depending on the receptors functional properties. GluN2B-NMDA receptors have a higher affinity for glutamate. [140] Extrasynaptic NMDA receptors have higher levels of GluN2B-containing heterodimers, are distinct, and probably serve a specific function. [16] The GluN3-containing NMDA receptors are not as common as those composed only of GluN1 and GluN2 subunits. [139] In the CNS, they are important in delaying synapse maturation until the arrival of sensory experience and in targeting non-used synapses for pruning. Reactivation of GluN3A expression at the wrong time may result in neuropathology. [141]

Kainate receptors

Another member of the ionotropic glutamate receptors, kainate receptors, form from 5 subunits (GluK1, GluK2, GluK3, GluK4, and GluK5) into tetrameric ion channels. GluK1-3 can form homomeric and heteromeric receptors whereas GluK4-5 must form heteromeric receptors with one of the GluK1-3 subunits to form functional channels. [142],[143],[144],[145],[146] The former are low-affinity kainate receptors and the latter high-affinity kainate receptors. [147] GluK5 is widely distributed through the CNS and in heteromeric complexes with GluK2 constitutes the most abundant kainate receptor subtype in the brain. [146],[147]

Located at pre- and postsynaptic membranes of neurons and astrocytes in the CNS, kainate receptors are constituents of excitatory synaptic transmission and modulation of excitability by regulating neurotransmitter release. In an experimental mode of temporal lobe epilepsy, Vargas et al showed an increase in astrocyte expressed kainate receptor subunits (GluK1, GluK2, GluK3, GluK4, and GluK5) following status epilepticus. The authors suggested that this may serve as a sensor for excess glutamate. [148] Astrocyte response to extracellular glutamate is propagation of intracellular Na + waves resulting in activation of glial Na + /K + -ATPase which increases energy demand inside the astrocyte. [149] Increased energy demand and glucose consumption inside the astrocyte provides metabolic substrates to neurons through the astrocyte-to-neuron lactate shuttle and provide energy substrates for injured surviving neurons. [150] Functioning kainate receptors may also trigger release of gliotransmitters - glutamate release from astrocytes has been implicated in hippocampal slice models of seizure activity. [158],[159] Increased Ca 2+ signaling, hypothesized to result from pathological expression of kainate receptors in reactive astrocytes, may cause synchronization of neurons due to glutamate and result in hyperexcitability. Both may contribute to the pathophysiology of epilepsy [151],[152] and differences in NMDA receptors and kainate receptors in astrocytes are associated with delayed neuronal death in the injured brain - functional astrocyte loss is considered a cause of neuronal death in the injured CNS as vulnerability of astrocytes to NMDA and kainic acid are associated with delayed neuronal death. [153] Partially Ca 2+ -permeable, kainate receptor activation also results in an influx of Ca 2+ ions and the resulting Ca 2+ waves within the astrocytic syncytium may lead to the release of gliotransmitters from astrocytes. [154],[155] In hippocampal neurons, released glutamate triggers a slow, transient, current which can activate NMDA receptors [156] and/or activates GluK5-containing kainate receptors on interneurons and increases inhibitory postsynaptic currents. [147]

Delta receptors

GluD1 and GluD2 form this iGluR sub-family because of sequence homology. Recent animal studies show that these receptors are upregulated during postnatal development and play a role at excitatory synapses in neuronal networks in the adult brain. [157] GluD1 is predominately expressed in the inner ear and is important for high-frequency hearing and GluD2 is predominatenly expressed in cerebellar Purkinje cells and is important for motor coordination and motor learning. GluD2 contribute to synaptic formation through interaction with cerebellin precursor protein 1 and presynaptic Neurexin. The latter binds to the N-terminal domain of GluD2 and regulates formation and maintenance of parallel fiber-Purkinje cell synapses. Both receptors are widely expressed in other brain regions. [158],[159],[160],[161]

These delta receptors possess functional ion channel pores, but ligand binding at the ligand-binding domain may only result in desensitization-like conformation channels. Receptor domains, except the ligand-binding domains, of GluD1 and GluD2 are capable of ligand-gated ion channel function. [162] GluD1 regulates the connectivity of parallel fiber-interneurons synapses and this results in differentiation and/or survival of molecular layer interneurons. This is done with the help of GluD2 and results in cerebellar synaptic wiring. [163],[164] Glutamate binding to mGlu1 has also been shown to result in GluD2 ion channel activity and contributes to slow excitatory postsynaptic currents in Purkinje cells. [165] An allosteric interaction between amino-terminal domain and ligand-binding domain layers for GluD2 is thought to be due to anchoring of GluD2 to the Nrx-Cbln1 complex which limits motion of the amino-terminal domain layer and allows D-serine-induced conformational changes to be transmitted to the TMD and C-terminal domain.

Glutamate G-protein-coupled receptors

As the most abundant receptor gene family in the human genome, GPCRs are membrane bound proteins activated by extracellular ligands through interactions with G proteins - a family of proteins that act as molecular switches inside cells and are regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate to guanosine diphosphate. Conformational changes of the GPCR result in activation of the G protein which is composed of a heterotrimeric complex of α, β, and γ subunits. Activation of G protein subunits then modulates the function of effector molecules. The GPCR family has several subgroupings, the majority of classical neurotransmitter GPCRs belonging to family A. mGluRs belong to Class C GPCRs which also includes GABAB receptors, calcium-sensing receptors, pheromone receptors, and taste receptors. [166],[167]

Eight mGluR subtypes have been identified and are subclassified into three groups based on sequence homology, G-protein coupling, and ligand selectivity. mGluRs 1 and 5 are in Group I, mGluRs 2 and 3 in Group II, and mGluRs 4, 6, 7, and 8 in Group III. Groups I and II are present in neurons with mGluR3 and mGluR5 also being present in astrocytes. Group III mGluR are not present in astrocytes, are predominantly presynaptic, and mGluR6 expresses its effects in retina. Signaling pathways of Group I mGluR include phospholipase C stimulation, stimulation of adenylyl cyclase, and MAP kinase phosphorylation, that of Group II include inhibition of adenylyl cyclase, activation of K + channels, and inhibition of Ca 2+ channels, and that of Group III include inhibition of adenylyl cyclase, activation of K + channels, and inhibition of Ca 2+ channels (The mGluR6 in the retina initiates a signal transduction cascade used by depolarizing bipolar cells to convey the light-induced decline in photoreceptor glutamate release to retinal ganglion cells). mGluRs contain a large extracellular N-terminal domain, the Venus flytrap domain (VFD), has two lobes and bind glutamate in a cleft between them. This dimer may be open-open (inactive), open-closed, or closed-closed. The latter two are induced by binding of ligand. VFD's can also bind divalent cations which can potentiate or activate the receptor. The signal induced by ligand binding is transmitted from the VFD's through cysteine-rich domains. A disulfide bridge linking the VFD and cysterine-rich domain may be required for propagation of signals induced by agonist binding to mGluRs. The heptahelical domain of the mGluRs may regulate G protein coupling specificity. Modulators of mGluRs affecting glutamate activity bind within the hepatohelical domain and may positively or negatively influence glutamate activity. Modulation of G protein coupling also occurs at the C-termini of mGluRs. [167]

Activation of mGluR by glutamate may require binding of both protomers, may depend on the mGluR group, and result in Ca 2+ mobilization and activation of protein kinase C. Ion channels on the plasma membrane are indirectly activated through a signaling cascade involving G proteins. Binding of glutamate to mGluR1 results in an increase in Ca 2+ in the cytoplasm, that of mGluR5 release of K + from the cell by activating K + channels, that of mGluR2 and mGluR3 result in inhibition of adenylyl cyclase causing shutdown of the cAMP-dependent pathway and thereby decreasing the amount of cAMP, and that of mGluR4, mGluR6, mGluR7, and mGluR8 result in activation of Ca 2+ channels allowing more Ca 2+ to enter cells. [168],[169],[170],[171],[172]

Glutamate transporters

Excitatory signaling, neurovascular coupling, glutamate/metabolic pathways, glycolytic enzymes/glycolysis, mitochondria/oxidative phosphorylation, glycogen phyosphorylase/glycogen synthetase, Na + /Ca 2+ exchangers, and Na + /K + -ATPase depend on glutamate transporters that are present on astrocytes and neurons. Critical for normal brain function, the family of brain glutamate transporters includes excitatory amino acid transporters 1 to 5 (EAAT1-5). All transport L-glutamate and, during one transport cycle, the transporter binds one extracellular molecule of glutamate, three sodium ions, and one proton. Conformational changes result in these substrates being released into the cytoplasm. To complete the cycle, a potassium ion in the cytoplasm is bound to the transporter and conformational changes result in the potassium being released into the extracellular space. EAAT's can also function as chloride channels and may be considered inhibitory glutamate receptors. [173],[174],[175] EAAT1 (GLAST) and EAAT2 (GLT-1) are mainly located on astrocytes. EAAT3-5 are exclusively neuronal.

Synaptic transmission is dependent on extracellular glutamate concentration. Impaired GLT-1 results in an increase in extracellular glutamate levels and, in GLT-1 knockouts, result in hyperactivity and severe seizures. [176],[177] In animal models, astrocytic GLT-1 and neuronal GLT-1 are different and abnormalities result in distinct clinical patterns. [177] GLAST-deficient mice display longer seizure duration. Human mutations are associated with ataxia and seizures. [178],[179],[180] While neuron-specific glutamate transporters are not important for survival, behavioral abnormalities have been observed. [181],[182] Although diffusion is the major mechanism governing synaptic glutamate concentration, glutamate transporters are also key regulators of synaptic transmission and termination of transmission. Glutamate existence in the synaptic cleft is short, about 1.2 ms, and concentration is high, 1 mM. While AMPA- and NMDA-glutamate receptors become desensitized with prolonged exposure to the neurotransmitter, glutamate transporters actively control duration of excitatory transmission by competing for glutamate in the synapse and is related to astrocytic coverage of synapses - controls presynaptic glutamate receptor activation through glutamate uptake. Critical during high activity and/or multisynapse transmission, glutamate transporters control glutamate receptor activation and spillover of glutamate between synapses and, thus, maintain specificity of synaptic transmissions.

 What Happens With Too Much Glutamate In The Central Nervous System?

Glutamate excitatory signaling is needed for most motor, sensory, and autonomic processing, memory formation, and normal brain development - physiologic activity being determined by the balance of synaptic excitation and inhibition (the E/I balance). Glutamate, the predominant excitatory neurotransmitter in the CNS, is normally restrained by inhibitory mechanisms, but an increase in the number of glutamate synapses, enhanced glutamate synaptic function, and/or increased extracellular glutamate concentrations result in an imbalance and the excess glutamate effect may result in massive neuronal death and brain damage due to excitotoxicity. Control of glutamate clearance which results in low extracellular glutamate and less excitotoxicy is an important function of astrocytes. [183] Astrocytes have receptors regulated by the neurochemical environment that allow them to determine neuronal transmission. Activation of these receptors results in changes of ion concentrations (mainly Ca 2+ and Na + ) in the cytoplasm of the astroglia which regulate astroglial functions and act as a substrate for astroglial excitation. [184],[185],[186],[187],[188] Complex interactions between the blood vasculature, interposing cerebrospinal fluid, and surrounding interstitial fluid are facilitated by astrocytes as well and influence neurotransmitter concentrations. [188] Glutamate homeostasis determined by astrocytes in these dynamic processes is not well defined.

Although synaptogenesis and synaptic maturation proceed through formation of an initial contact between the terminal and postsynaptic neuron, maturation of the synapse, stabilization and maintenance, and elimination, survival time and contribution of synapses varies. Control of extracellular glutamate and neuronal glutamate pools by astroglia regulate extracellular glutamate concentration by balancing uptake through Na + -dependent astroglia-specific glutamate transporters (SLC1A3/EAAT1 and SLC1A2/EAAT2) and release mainly through the cysteine-glutamate exchanges of systemic Xc - (SLC7A11). The astroglial cradle regulates these processes and isolates synapses within the territory of a single astrocyte and prevents neurotransmitter spill-in and spill-over. While point-to-point transmission of glutamate across a synapse has been the conventional view of glutamate neurophysiology, glutamate spillover due to escape of glutamate from the synaptic cleft results in glutamate accumulating in the extrasynaptic space as well. Glutamate concentrations vary greatly between plasma, cerebrospinal fluid, intracellular fluid, and extrasynaptic fluid. Computational models suggest that extracellular glutamate concentrations are regulated differently in the synaptic, perisynaptic, and nonsynaptic subcompartments and regulates or results in pathology of synaptic transmission, synaptic plasticity, synaptic crosstalk, nonsynaptic neurotransmission, neuronal survival, gliotransmitter release, and/or hemodynamic responses. [189],[190],[191],[192],[193]

E/I imbalance contributes to acute and chronic CNS neurodevelopmental and neurologic disorders. If extracellular glutamate rises to above normal, glutamate receptors are overactivated and intracellular reactions in the postsynaptic neurons result in cell injury and possibly death due to excitotoxicity. Astroglial glutamate transporters coordinate this excitatory signaling and brain energetics. These transporters co-localize with, form physical interactions with, and couple to energy-generating systems (Na + /K + -ATPase, Na + /Ca 2+ exchanger, glycogen metabolizing enzymes, glycolytic enzymes, and mitochondria/mitochondrial proteins). Glutamate uptake regulates these processes and the process may regulate glutamate uptake. [191] Transporters remove the extra extracellular glutamate via a sodium-potassium couple uptake mechanism. If not removed, excess glutamate has been associated with neural damage and results in high levels of Ca 2+ to influx into the postsynaptic cells. Cell degradation due to proteases, lipases, nitric oxide synthetase, and enzymes that affect cell structures results. A cycle of positive feedback cell death can lead to neurodegeneration. Oxidative stress is also affected. High synaptic glutamate levels reverse cysteine/glutamate antiporter (transports cysteine into the cell and glutamate out). Glutathione, an antioxidant, is not synthesized at the appropriate levels. This leads to more ROS that injure the cells which then cannot process glutamate. Nitric oxide synthase is also activated by the high concentration of glutamate with a resulting over production of nitric oxide - damages mitochondria. Astrocyte homeostasis of glutamate is important in regulating these complex interactions. [181],[182],[183],[184],[185]

 Possible Biochemical Effects Of Carbon Monoxide On Astrocyte Glutamate Homeostasis

CO is a gasotransmitter: 1) It is a small molecule of gas; 2) It is freely permeable to membranes; 3) It can have endocrine, paracrine, and autocrine effects; 4) It is endogenously and enzymatically generated and its production is regulated; 5) It has well defined and specific functions at physiologically relevant concentrations; and 6) Its cellular effects may or may not be mediated by second messengers, but have specific cellular and molecular targets. CO is cytoprotective and at least 86% originates from heme metabolism. Heme-independent sources include auto- and enzymatic-oxidation of phenols, photo-oxidation of organic compounds, iron-ascorbate catalyzed lipid peroxidation of microsomal lipids and phospholipids, and reduction of cytochrome b5. Endogenous CNS CO is critical for the normal functioning, neuroprotection, and neurorepair of the brain. Synthesis, transactions, and disposition are clinically relevant for neurodevelopment, neuropathology, and neurotherapy. A neurotransmitter, endogenous CO is dependent on brain heme oxygenase isozymes, heme oxygenase-1 (HO-1) (primarily localized in the endoplasmic reticulum) and heme oxygenase-2 (HO-2) (primarily anchored to the endoplasmic reticulum). These catalyze the first and rate-limiting step in the degradation of heme to iron, biliverdin, and CO. CNS cytoprotective effects are attributed to CO [194] and are mimicked by low dose exogenous CO (inhaled CO and CORM's). Increased CO production by upregulation of heme oxygenases has been targeted for neuroprotective and neurotherapeutic effects and exogenous administration of CO or CORM's and/or targeting of heme oxygenases to increase the production of CO have been suggested as treatment for multiple CNS disease processes. [195],[196],[197],[198],[199],[200],[201],[202],[203],[204],[205]

CNS CO signal transduction pathways result in vasoactive, antithrombotic, anti-proliferative, neurotransmission, anti-inflammatory, and/or anti-apoptotic effects. [206] CO interaction with soluble guanylate cyclase (sGC) via the sGC/cGMP pathway is associated with vascular effects (platelet aggregation, dilation, profibrinolysis, and anti-inflammation) and downregulation of cell proliferation. In the latter, CO upregulates the p38 mitogen activated protein kinase (p38β MAPK) and p21 resulting in downregulation of cell proliferation. CO effects on p38β MAPK affect apoptosis (through antiapoptotic genes and caspase activation) and inflammation (through heat shock factor-1, interleukin-10, interleukin-1β, interleukin-6, tumor necrosis factor-α, and macrophate inflammatory protein1β). [206] Induction of the heme oxygenases has resulted in elevated CO levels and are thought to be neuroprotective as well as neurotherapeutic.

As astrocytes are critical for the homeostasis of glutamate and resultant excitotoxicity and neuropathology, further evaluation of CO effects on astrocytes and the biophysiological interactions affecting glutamate homeostasis is needed. CNS astrocytes are now targeted for treating neurological disorders as non-neuronal cells (which include astrocytes) outnumber neurons, vesicle-based release of transmitter is present in astrocytes although the kinetics is slower than in neurons, and astrocytes contain glycogen which is converted into L-lactate, a fuel and signalling molecule important to cognition and neuroprotection and an alternative energy source during excitotoxic brain injury. CO is thought to increase L-lactate. [207] Exposure of cortical neurons to glutamate increases HO-2 activity and CO production. Upregulation of CNS HO-1 also results in an increase of CO. Astrocyte heme oxygenases can also be upregulated thereby increasing the production of CO. Diffusion of the gas to different cell types and cell organelles result in effects on biochemical pathways. The effects of CO on astrocyte homeostasis of glutamate and prevention of excitotoxicity with resultant neuropathology, most likely, involve multiple pathways as well as intra and extracellular structures that result in communication between cells and within cells. [206],[208],[209],[210],[211],[212].[213],[214],[215],[216] Important for CNS homeostasis, astrocyte glutamate metabolic pathways, uptake of glutamate by astrocytes, and release of glutamate from astrocytes are affected by the presence or absence of CO.

Glutamate metabolic pathways

Cellular energy

Mitochondrial energy production is modulated based on cellular needs and bioenergetic constraints. ATP is responsible for most of the energy in cells. Mitochondrial respiration determines, to a large extent, this cellular energy, depends on oxidative phosphorylation (consists of the electron transport chain (ETC) and ATP synthase), and plays an important role in energy production and apoptosis. [217],[218],[219]

Regulation of the mitochondrial ETC and ATP synthase (result in the majority of cellular energy through cell signaling) limit reactive oxygen species (ROS) responsible for cell damage and the triggering of death processes, oxidative phosphorylation activity, mitochondrial membrane potential hyperpolarization, release of CytC, formation of the apoptosome, and execution of apoptosis via caspase activation. Bioenergetic defects, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increased sensitivity to apoptosis, and the accumulation of damaged mitochondria with unstable mitochondrial DNA have been associated with energy defects. Mitochondria regulate Ca 2+ signals and ionic homeostasis, synaptic development, blood flow, glucose metabolism, glutamate clearance, plasticity, proliferation, coordinate local metabolism, provide energy, are dynamic, and integrate survival and death biochemical changes. There is extensive fission and fusion of these organelles, directed movement within cells, and controlled degradation. The former is critical for development of the CNS and determine the shape, connectivity, distribution, and density of mitochondria within neurons and, probably, astrocyte processes. In astrocytes, mitochondria are seen within the finer processes of the cell, movement is regulated, and they contribute to local Ca 2+ signaling within the astrocyte. Protoplasmic astrocytes have highly branched processes and veil-like structures resulting in a very large surface area to volume ratio and intimate association with synapses (may exceed 2 million synapses in the human brain). [220] Astrocyte mitochondria are mobile (arrested by glutamate and Ca 2+ ), change speed and direction, and movement depends on adaptor proteins and motor proteins. [221],[222],[223],[224],[225],[226],[227] Mitochondrial movement in the astrocyte promotes distribution of mitochondria into cellular processes, allows retrograde movement out of the cell processes and into the cell body where degradation of mitochondria takes place, improves fusion and fission processes which allow exchange of proteins and genetic materials, promotes the regulation of transfer of mitochondria between adjacent cells (horizontal transfer), and redistribution of mitochondria to sites needing increased energy production is facilitated. [228],[229],[230],[231],[232]

Astrocyte mitochondrial presence and activity are related to neuronal activity and, especially, glutamatergic activity. Inhibition of neuronal activity increases activity of mitochondria in astrocytes. Mitochondria are not uniformly distributed in astrocytes and their location at synapses and active regions is associated with neuronal activity - about 15% of the astrocytic mitochondria are mobile. The addition of glutamate decreases the percentage of mobile astrocyte mitochondria in preparations. Glutamate, considered to be partly responsible for the mobility of astrocyte mitochondria, is cleared into astrocytes via GLAST and GLT1 (EAAT1 and EAAT2). These catalyze glutamate and aspartate transport against a concentration gradient with three Na + ions and a H + with the counter-transport of a K + ion. Na + /K + ATPase is activated which results in reversal of the Na + /Ca 2+ exchanger leading to increases in Ca 2+ . [233],[234],[235] Mitochondria movement is regulated by glutamate uptake and is directly related to the concentration of Ca 2+ . Inhibition of glutamate uptake increases mobile mitochondria in astrocyte processes. The movement of astrocyte mitochondria depends on cellular transport machinery, adaptor proteins that link mitochondria to motor proteins. Mitochondrial Rho proteins and trafficking kinesin binding proteins are thought to be important in the positioning of mitochondria to active processes in astrocytes. [236],[237],[238] Mitochondrial Rho proteins respond to Ca 2+ signaling - Ca 2+ results in the arrest of mitochondria within astrocyte processes in response to neuronal activity and glutamate. [226],[227],[237] Under normal conditions, mitochondria approach endoplasmic reticulum allowing Ca 2+ flow between organelles - close apposition is needed. Formation of tethers that link the mitochondria with endoplasmic reticulum may be dependent on Miro proteins [238],[239],[240] and affect other cellular processes.

CO targets mitochondria, including astrocyte mitochondria, at several levels: 1) Mitochondrial ROS, signaling molecules for CO-induced pathways, are increased with physiological amounts of CO; 2) CO limits mitochondrial membrane permeabilization and thereby inhibits the release of pro-apoptotic factors into the cytoplasm; 3) CO increases the ability of the mitochondria to take up Ca 2+ ; 4) CO modulates mitochondrial metabolism by increasing TCA cycle rate, oxidative phosphorylation and mitochondrial biogenesis which increases ATP; and 5) CO prevents excitotoxicity-induced cell death and modulates cell proliferation by limiting the activity of T-type and L-type Ca 2+ channels. [241],[242],[243],[244],[245],[246] CO, therefore, affects ROS signaling and anti-oxidation, Ca 2+ -induced mitochondrial membrane permeabilization, programmed cell death, Ca 2+ buffering, and metabolism. CO targets cyclooxygenase (COX), the final electron acceptor of the mitochondrial electron transport chain - catalyses oxidation of ferrocytochome c by gaseous oxygen. At high levels, CO results in high levels of carboxyhemoglobin which exceeds the limit of toxicity. However, at lower levels, COX-specific activity is dependent on oxygen concentration and may activate hypoxia-inducing factor-1 which is involved in the regulation of COX subunits for optimization of mitochondrial respiration. Hypoxia and CO presence have a synergistic effect on COX inhibition when the ETC is in a more reduced state. Low concentrations affect the coupling between ATP production and respiration. Cytoprotection is associated with mitochondrial mild uncoupling stimulation thus decreasing mitochondrial ROS production and is dependent on its concentration - at lower concentrations, increased respiratory control ratio and mitochondrial transmembrane potential are seen whereas, at higher concentrations of CO, a decrease in respiratory control ratio and mitochondrial membrane potential is seen. Brief exposure of astrocytes isolated from cortex increased cellular oxygen consumption with an improvement of mitochondrial respiratory chain and oxidative metabolism. CO also stimulates mitochondrial biogenesis, important for cell metabolism and cell protection, and regulates mitochondrial respiratory complexes. [247],[248],[249],[250],[251],[252]

Changes in astrocyte intracellular calcium occur with exposure to CO and/or glutamate. Two different pathways have been identified. With glutamate, the metabotropic response results in an initial Ca 2+ spike that can propagate rapidly from cell to cell and probably involves IP3. This can produce oscillatory intracellular waves that propagate within cells and are sustained only if external Ca 2+ is present. The second response, the ionotropic response, results in sustained elevation in Ca 2+ and is associated with receptor-mediated Na + and Ca 2+ influx, depolarization, and voltage-dependent Ca 2+ influx. CO, involved in Ca 2+ signaling and in the modulation of Ca 2+ channels, inhibits L-type Ca 2+ channels and may be cytoprotective. This has not been demonstrated in astrocytes. CO has also been implicated in preventing activity of T-type Ca 2+ channels, and regulation of intracellular organelle Ca 2+ stores. The direct effect of CO on Ca 2+ signaling in the astrocyte mitochondria is not known, but glutamate-induced calcium signals stimulate CO production in astrocytes. [235],[246],[253],[254],[255],[256] Further studies are needed to evaluate the role of CO in mitochondria and glutamate homeostasis.

Mitochondrial glutamate versus cytosol glutamate and carbon monoxide

Transport of keto acids, amino acids, nucleotides, inorganic ions, and co-factors across the mitochondrial inner membrane is dependent on the mitochondrial carrier family - mitochondrial glutamate pathways being controlled by mitochondrial enzymes and transmembrane carriers (especially GDH and mitochondrial glutamate carriers, respectively). Biochemical pathways between the cytosol and the mitochondrial matrix result and are essential for synthesis of ATP from oxidation of sugars and fats, synthesis of heme and iron sulphur clusters, production of heat, macromolecular synthesis, and the synthesis, degradation, and interconversion of amino acids. Regulation of GDH activity has been suggested as a neurotherapeutic approach - neuronal mitochondrial activity is improved and excitotoxic risk reduced with increased GDH activity. [256] Similar studies on astrocytes have not been done. The mitochondrial glutamate carriers, also important to glutamate homeostasis, consist of six trans-membrane α-helices and three matrix helices arranged with threefold pseudo-symmetry - substrate binding site is accessible from the intermembrane space of the mitochondrion. Required for normal CNS function, two aspartate-glutamate carriers (AGC: aralar and citrin) - opening and closing of the carrier and substrate binding may depend on disruption and formation of two salt bridge networks - and two glutamate/hydroxyl carriers (GC1 and GC2) are present in astrocytes.

The aforementioned AGC's are classified as strict exchangers or uniporters and are electrogenic. [257] Precursor proteins are synthetized in the cytosol and then are transported to mitochondria membranes. Astrocytes express both aralar and citrin - AGC1 (aralar) is important to glutamate-mediated excitotoxicity in the mature CNS and muscles. Both supply aspartate that is produced in the mitochondrial matrix to the cytosol in exchange for cytosolic glutamate plus a proton [258] and is important for the control of mitochondrial respiration and calcium signaling and antioxidant defenses. Ca 2+ on the external side of the inner mitochondrial membrane stimulates transport activity and the Ca 2+ -binding sites are localized and are independent of Ca 2+ entry into the mitochondria by calcium uniporter and activates the AGCs from the external face of the mitochondria. [259],[260] Glutamate delivered into the mitochondria through AGC's is transaminated with intramitochondrial oxaloacetate to form aspartate and is not available for GDH. GC1 and GC2, unlike the AGC's, function in forward or reverse mode and provide substrate for GDH. GC1 and GC2 are equally expressed in the brain. GC's are important in ureogenesis, glutamate derived from GC's produce NH 3 . Direction of transport of glutamate is dependent on the energy state of the mitochondria and is controlled by mitochondrial metabolism.

Aspartate, important to the homeostasis of astrocyte glutamate biochemical pathways, can only exit the mitochondria in exchange for glutamate. The former is expressed in the mitochondrial matrix of astrocytes. Normally, astrocytes metabolize glutamate via cytosolic GS resulting in glutamine. [259] When extracellular glutamate exceeds 0.5 mM, the amount metabolized via the TCA cycle in the mitochondria increases significantly and, if energy is needed, glutamate is metabolized primarily by GDH - glutamate enters the TCA cycle as α-ketoglutarate after deamination catalyzed by GDH and, ultimately, catabolism of glutamate to CO 2 with the production of ATP. Transport of glutamate from the cytosol across the mitochondrial membrane is by the AGC and the GC - AGC requires aspartate in exchange of glutamate and GC glutamate is transported with a proton. AGC requires a concentration gradient of solutes and/or electrochemical potential across the inner mitochondrial membrane and is a Ca 2+ sensor [259] which may be involved in Ca 2+ signaling. In addition to their role in glutamate and aspartate exchange, AGC 1 (Aralar1) and AGC 2 (citrin carriers) are part of the malate-aspartate shuttle that is needed for transfer of reducing equivalents from cytosolic NADH into mitochondria (and activates ETC) leading to ATP generation.

Calcium signaling is necessary to the function of GDH and the mitochondrial glutamate carriers. Matrix Ca 2+ is known to be important to mitochondrial function and the regulation of glutamate transport by extramitochondrial Ca 2+ may further determine their roles. AGC's are activated by low extramitochondrial levels of Ca 2+ . CO affects Ca 2+ concentrations and, therefore, probably GDH and mitochondrial glutamate carriers. Further studies are needed.

Precursors and intermediates

In the CNS, neurovascular coupling regulates energy supply required for fluctuating energy needs. Astrocyte-neuron metabolic cooperation result in spatial and temporal delivery, production, utilization, and storage of energy for the brain - astrocytes, glutamate, and CO are essential to this process. Astrocytic processes cover approximately 63% of capillaries, allow detection of neuronal activity (and, therefore, energy requirements), and affect local vascular supply which increases or decreases availability of energy substrates. Afferent activity results in release of excitatory neurotransmitters from presynaptic sites and results in an increase of astrocyte glutamate. Glutamate stimulates CO production by astrocytes which is needed for activating transient K Ca currents and single K Ca channels in myocytes in contact with astrocytes resulting in dilation of the vessel, increase in blood flow, and subsequent increased availability of energy sources when needed. [261],[262],[263] While glucose has been considered the obligatory energy substrate in adult brains via oxidative metabolism, other substrates from the blood (ketones, lactate, etc.) are also used as energy sources and may be preferred and are transported into both neurons and astrocytes. Nonoxidative metabolism for energy production may be important as well. [264],[265],[266] The metabolism of glucose to CO 2 and water may or may not result through glycolysis, the pentose phosphate pathway, and/or glycogenolysis as metabolic intermediates can also be oxidized as an energy source (i.e. lactate, pyruvate, glutamate, or acetate).

Glycogen, an energy substrate found predominantely in astrocytes, is broken down to lactate and is affected by neurotransmitters and glucose concentration and provides some neuroprotection during hypoglycemia and high levels of CNS activity. Lactate is considered to be neuroprotective and may be the preferred CNS energy substrate. Interestingly, glutamate stimulated CO production by astrocytes with intact heme-oxygenase 2 also affects L-lactate levels in astrocytes suggesting an association between L-lactate and heme oxygenase neuroprotective systems. The cell specific metabolic profile of astrocytes is different from that of neurons and there are different expressions of enzymes that regulate cell metabolism including glycogenolysis and glycolysis. Intercellular lactate shuttles transferring lactate from lactate-producing cells to lactate-consuming cells exist between astrocytes and neurons - a lactate gradient from astrocytes to neurons allows for a carrier-mediated lactate flux from astrocytes to neurons and astrocyte-derived lactate can be used as an energy substrate for neurons. [267],[268] Anaerobic glycolysis results when pyruvate is acted on by lactate dehydrogenase to form lactate and aerobic glycolysis when a cell specific gene expression profile that affects conversion of pyruvate to lactate as opposed to pyruvate being used in the TCA cycle. Transport of glucose across the blood brain barrier is ten times higher for glucose than for lactate and astrocytes (in an activity dependent manner) determines CNS lactate formation by an uncoupling between glycolysis and the TCA cycle. Studies are needed to further define the role of lactate in neuroprotection, effect of CO on production of lactate and other metabolic substrates in astrocytes, use of lactate as an energy substrate by astrocytes and neurons, transport of lactate from astrocytes to neurons, and metabolism of various metabolic substrates to lactate.

Uptake of glutamate by astrocyte

Failure of sodium homeostasis, due to reduced ATP, results in extra- and intracellular changes of potassium, calcium, and protons and, therefore, changes in excitotoxicity. Astrocyte metabolism and sodium homeostasis is dependent on glutamate uptake and is critical to maintaining sodium homeostasis and energy levels of surrounding neurons. A major determinant of uptake of glutamate by astrocytes is the transmembrane Na + gradient controlled by NaK-ATPase (NKA). The latter has three subunits - α, β, and γ with 4 isoforms of the α subunit. Astrocytes express α1 and α2 subunits and, in the brain, the α2 isoform is mainly expressed in astrocytes. CO regulates NKA through cGMP and protein kinase G (PKG) and glutamate regulates CO through mGluRs. [263],[265] NKA has been estimated to be responsible for nearly 50% of the cellular ATP hydrolysis linking cellular sodium regulation and energy metabolism in the CNS. Decreased NKA activity results in energy deficiency and has been associated with neurodegenerative diseases. [265],[266],[267],[269],[270],[271],[272],[273] Upregulation or downregulation of astrocyte production of CO to affect sodium homeostasis and energy levels of neurons needs further evaluation as the interactions between astrocytes, glutamate, and CO directly affects neurons, CNS health, and pathologies of the CNS.

Release of glutamate from astrocyte

Ca 2+ -dependent exocytosis

Exocytosis of glutamate, one of the mechanisms of astrocytic glutamate release, is largely dependent on soluble N-ethylmaleimide-sensitive-factor attachment protein receptor proteins (regulators of exocytosis) and is Ca 2+ -dependent. Extracellular signaling molecules result in an increase in Ca 2+ concentration in the cytosol and, triggered by an increase of cytosolic Ca 2+ (mainly from endoplasmic reticulum stores), exocytosis of glutamate results with the merger of gliosignal-containing vesicles with the plasma membrane and membrane associated molecules. [274],[275],[276],[277],[278] Released astrocytic glutamate reacts with receptors on synaptic terminals and excitability of neurons is seen. Mitochondria have a Ca 2+ uniporter that transports Ca 2+ into the mitochondrial matrix when cytosolic Ca 2+ is greater than about 0.5 µM which, when blocked, increases cytosolic Ca 2+ and glutamate release. [241],[279] CO decreases the activity of L- and T-type Ca 2+ channels, probably affects Ca 2+ signaling between endoplasmic reticulum and mitochondria, regulates the mitochondrial calcium uniporter and regulates mitochondrial Ca 2+ concentrations. [241],[272],[243] Ca 2+ regulation by CO, therefore, affects Ca 2+ -dependent exocytosis and requires further study.

Intracellular calcium concentration

Astrocytes, activated during physiological functioning of the CNS, release glutamate in response to an increase in Ca 2+ , but Ca 2+ concentration in astrocytes does not result in on/off responses but rather in different and graded functions depending on the need of the cell - the type of neuronal input is important to the type of astrocytic Ca 2+ response. Reactions vary in the different organelles. Ca 2+ enters the cell through Ca 2+ channels in the plasma membrane or store-operated Ca 2+ channels. Sources include the extracellular space and the endoplasmic reticulum/sarcoplasma reticulum. Mitochondria Ca 2+ uptake is efficient and is mainly via a mitochondria Ca 2+ uniporter (MCU or CCDC109A). [278],[279] Ca 2+ crosstalk with the plasma membrane is important for cellular functions. Within mitochondria, Ca 2+ activates three dehydrogenases (pyruvate dehydrogenase, oxoglutarate dehydrogenase, and isocitrate dehydrogenase) in the mitochondrial matrix, stimulates production of ROS, results in opening of mitochondrial permeability transition pores and possibly regulates Fl-Fo ATP synthase. [280],[281],[282],[283] Efflux of the ion from mitochondria is primarily determined by Na + -dependent and Na + -independent pathways. Astrocyte mitochondrial Na + -Ca 2+ exchanger is important for store-operated Ca 2+ entry indicating communication between mitochondria and the plasma membrane. CO is essential to the observed effects of intracellular Ca 2+ concentration on cellular functions - CO stimulates astrocytic mitochondrial biogenesis via L-type Ca 2+ channel-mediated peroxisome proliferator-activated receptor-gamma coactivator -1alpha/estrogen-related receptor α activation and through potentiation of L-type Ca 2+ channel activity increases hypoxia-inducing factor-1α-independent vascular endothelial growth factor expression via an AMP-dependent protein kinaseα/sirtuin1-mediated peroxisome proliferator-activated receptor-gamma coactivator -1alpha/estrogen-related receptor α axis. [283],[284] Other effects of CO on intracellular Ca 2+ need further evaluation.

Potassium channels

Astrocytes may serve as excitatory interneurons that affect synchrony of a set of neurons. [45],[47] Modulation of excitability and synchronization of neuronal activity and network oscillations through the effect of K + may be partially regulated through Ca 2+ -dependent release of glutamate (activate extrasynaptic NMDA receptors) that depends on K + . Extracellular K + concentration and astrocyte depolarization also affect glutamate uptake through glutamate transporters - inverse glutamate uptake and vesicular glutamate release may affect synchrony of neurons and is affected by K + buffering by astrocytes. [285],[286] Uptake of excess extracellular K + released during neuronal discharge is important to the regulation of extracellular K + that regulates neuron membrane potential and subsequent excitability. Diverse astrocyte K + channels mediate these K + currents.

Astrocytes express various K + channels that depend on CNS development and region of the brain with specific subcellular types that include inward rectifying K + (Kir) channels (Kir4.1, Kir5.1, and Kir6.1 present in astrocytes), two-pore-domain K + (K 2P ) channels (TASK1, TREK2, TREK1, and TWIK1), Ca 2+ activated K + channels, and Kv channels (Kv1 to Kv12 which include channels affected delayed rectifier (K DR ) and transient (KA ) currents). [285],[286],[287],[288][289],[290] The channels are involved in processes that depend on transmembrane voltage, i.e., Kir4.1 sets the resting potential of astrocytes and is responsible for the large inward currents recorded at negative membrane potentials, TASK1 may inhibit cellular swelling under ischemic conditions, [291] BK channels depend on membrane potential and intracellular Ca 2+ concentration, and Kv channels are expressed perinatally. Astrocyte K + conductance is dominated by the Kir channels. [292],[293],[294],[295],[296],[297]

Outside of the CNS, CO interacts with K + channels. [298],[299] In vascular smooth muscle K (Ca) channels are activated and a specific target of CO is the histidine residue. Activation of ATP-sensitive K + channels results in the peripheral antinociceptive effect of the HO/CO pathway. CO inhibits the voltage-gated K + currents in the medulloblastoma cell line DAOY and reverses the oxidant-induced increase in K + activity. [300] CO results in inhibition of recombinant Kv2.1 expressed in HEK293 cells. These K + channel effects have not been studied in astrocytes and deserve further evaluation.

Sodium dependent glutamate transporters

Astrocytic, not neuronal, glutamate transporters are important to maintaining extracellular glutamate concentrations, are needed for brain development through regulation of extracellular glutamate concentrations, and modify metabolic communications between neurons and astrocytes. The majority of these physiologic processes (neurovascular coupling, excitatory signaling, Na + /Ca 2+ exchangers, Na + /K + ATPase, glycogen phosphorylase/glycogen synthase, mitochondria/oxidative phosphorylation, glycolytic enzymes/glycolysis, and glutamate/metabolic pathways) are mediated by GLT-1 and GLAST (EAAT1 and EAAT2) - astroglial glutamate transporters - and co-localize with, form interactions with, and couple to energy-generating systems. Primary functions of EAATs (sodium-dependent glutamate transporters) include maintaining extracellular glutamate concentration in the low micromolar range which allows glutamate to be used as a signaling molecule while preventing cytotoxic effects and controlling antioxidant defenses and metabolic roles of transported substrates. Binding of glutamate is rapid and buffering after entry into the extracellular space results. Responses are dynamic and depend on the location of the transporters. Uptake of glutamate is via co-transport of three sodium ions and one proton with counter-transport of one potassium ion. Energy is released and active transport of glutamate results. If extracellular glutamate uptake by astrocytes is reduced, excitotoxicity occurs. After uptake, glutamate is directed into different enzymatic pathways and may result in energy production and glutamine production. Activity of EAATs is closely coupled to glutamine release by astrocytes. [301],[302],[303],[304],[305]

Astrocyte GLAST and GLT-1 are responsible for the clearing of extracellular glutamate. In a hippocampal astrocyte culture from adult and aged rats, decreases in GLAST and GLT-1 were associated with decreases of nuclear factor E-2 related factor 2 (Nrf2) - regulates the transcription of HO-1 and, therefore, CO production which probably mediates neuroprotection. [306],[307],[308],[309] Further studies are needed to evaluate the relationship between Nrf2, HO-1, CO, GLAST and GLT-1.

Glutamate-gated ion channel receptors

Astrocyte glutamate signaling follows binding of glutamate to iGluRs and/or mGluRs and can lead to calcium signaling and subsequent glial excitability. Although the former is ubiquitously expressed in all neural cell types, iGluR subunit composition (18 iGluR receptor subunits) and subtypes differ between species, CNS cell types and brain areas, and change during development. Presence is not all or none, but rather quantitative, and developmental patterns are unique. A primary function is sensing and responding to neuronal release of glutamate - differences exist between astrocytes, types of iGluRs present, area of the brain, and other biochemical reactions present in the area. Heterogeneity in the function of iGluRs may result from differential expression of subtypes. AMPAR are mainly responsible for fast excitatory synaptic transmission and synaptic plasticity, NMDAR for excitatory synaptic transmission, plasticity, and excitotoxicity, and kainate receptors for regulating activity of synaptic networks and synaptic plasticity in the hippocampus and sensory cortex, but delta receptors (belong to the iGluR family because of sequence homology) function as ion channels only after interaction with other types of membrane proteins. [310],[311],[312],[313],[314],[315],[316],[317]

Apolipoprotein E (ApoE) affects these iGluR functions. ApoE, the major apolipoprotein in the CNS interaction with other types of membrane proteins (predominantly synthesized by astrocytes), reduces the level of extracellular glutamate and iGluR activation and, possibly, glutamate induced excitotoxic damage and protects astrocytes from hypoxia and glutamate-induced apoptosis. Nrf2 is increased in the presence of ApoE. The downstream target of Nrf2, heme oxygenase (and, therefore, CO production), is essential for cytoprotection. [318],[319],[320],[321],[322],[323] Studies have not been done evaluating the effect of ApoE on astrocyte glutamate and iGluR activation, Nrf2 production, and upregulation of heme oxygenase and CO production and their interrelationships and are needed to further define the role of upregulation of CO by ApoE on neuroprotection.

Calcium permeability of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors and GluA2

Subunit composition of AMPA receptors is dynamic and changing. Their Ca 2+ permeability and resulting action potentials are reflected in the output of neurons, normal synaptic functions and disease. Functional differences result in differences in excitatory signaling. Ca 2+ permeability is related to the GluA2 subunit which may be subjected to RNA editing by the ADAR2 enzyme - edited GluA2 subunits render the AMPA receptor impermeable to Ca 2+ . Change in number of AMPA receptors and GluA2 inclusion results in a change in AMPA receptor Ca 2+ permeability and, therefore, synaptic transmission and intracellular signaling. GluA2 mRNA and GluA2 subunit expression are downregulated in neurons prior to cell death. The "GluA2 hypothesis" suggests that reduction of GluA2 results in more Ca 2+ influx through newly synthesized AMPA receptors and, thereby, results in neurotoxicity secondary to glutamate. Unedited GluA2 results in AMPA receptors that are permeable to Ca 2+ . Blocking the formation of GluA2-less receptors, blocking GluA2-less receptors, and blocking of resulting apoptosis are approaches used to reduce neurotoxicity. As in neurons, Ca 2+ influx results in astrocytic Ca 2+ signaling. AMPA-evoked Ca 2+ influx into astrocytes has been associated with a weak expression of GluA2. [324],[325],[326],[327],[328],[329],[330] CO has a pivotal role in calcium signaling in both neurons and astrocytes. The role of astrocytic GluA2 in glutamate related neurotoxicity and calcium signaling and CO on these interactions needs further study.


Our understanding of the role of astrocytes in protecting the brain continues to result in methodologies in prevention and treatment of disease processes of the CNS. Astrocyte homeostasis of glutamate is crucial to CNS development, neurophysiology, and neuroprotection and has been targeted for neurotherapy. The role of CO in this homeostatic function is complex and is now being seen as obligatory. Upregulation of heme oxygenases and/or treatment with CO are being suggested as therapies for a wide range of neuropathologies. Limited knowledge of the effects of this important gasotransmitter on CNS biophysiology affects our ability to intervene on our patient's behalf. Research, however, is suggesting that astrocytes, glutamate, and CO are interacting and affect the CNS. Preconditioning with CO may lead to a change in substrate utilization in the brain of newborn piglets undergoing deep hypothermic circulatory arrest. [331] Loss of CO production and pial arteriolar dilation following astrocyte injury suggests that astrocytes may employ CO as a gasotransmitter for glutamatergic cerebrovascular dilation. [320] Inhibition of synaptosomal glutamate uptake by CO in a time-, dose-, and temperature-dependent manner was shown in the striatum and hippocampus. [332] In newborn pigs, the astrocyte component of the neurovascular unit is responsible for the vasodilation response of pial arterioles to topically applied glutamate via iGluRs functionally liked to activation of constitutive heme oxygenase. [333] Glutamate elevates Ca 2+ (i) in astrocytes leading to Ca 2+ - and calmodulin-dependent HO-2 activation, and CO production. [334] These and other effects of CO on astrocyte homeostasis of glutamate requires further evaluation and delineation. Results may lead to a simpler and better understanding of the role of CO in normal and abnormal astrocyte/glutamate interactions and result in medical interventions that limit or cure disease processes in the CNS.

Author contributions

The author completed the manuscript independently.

Conflicts of interest

The author has no conflicts of interest.

Financial support


Copyright license agreement

The Copyright License Agreement has been signed by the author before publication.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.


1Chilton CK. Molecular mechanisms of axon guidance. Dev Biol. 2006;292:13-24.
2Creeley CE. From drug-induced developmental neuroapoptosis to pediatric anesthetic neurotoxicity-where are we now? Brain Sci. 2016. doi:10.3390/brainsci6030032.
3Dekkers MPJ, Nikoletopoulou V, Barde Y. Death of developing neurons: new insights and implications for connectivity. J Cell Biol. 2013;203:385-393.
4Jansson LC, Åkerman KE. The role of glutamate and its receptors in the proliferation, migration, differentiation and survival of neural progenitor cells. J Neural Transm. 2014;121:819-836.
5Kroon T, Sierksma MC, Meredith RM. Investigating mechanisms underlying neurodevelopmental phenotypes of autistic and intellectual disability disorders: a perspective. Front Syst Neurosci. 2013;7:75.
6Marin O, Valiente M, Ge X, Tsai LH. Guiding neuronal cell migrations. Cold Spring Harb Perspect Biol. 2010;2:a001834.
7Meredith RM. Sensitive and critical periods during neurotypical and aberrant neurodevelopment: a framework for neurodevelopmental disorders. Neurosci Biobehav Rev. 2015;50:180-188.
8Garcia-Cabezas MA, John YJ, Barbas H, Zikopoulos B. Distinction of neurons, glia and endothelial cells in the cerebral cortex: an algorithm based on cytological features. Front Neuroanot. 2016;10:107.
9Bjørn-Yoshimoto WE, Underhill SM. The importance of the excitatory amino acid transporter 3 (EAAT3). Neurochem Int. 2016;98:4-18.
10Danbolt NC, Furness DN, Zhou Y. Neuronal vs glial glutamate uptake: resolving the conundrum. Neurochem Int. 2016;98:29-45.
11McKenna MC, Stridh MH, McNair LF, Sonnewald U, Waagepetersen HS, Schousboe A. Glutamate oxidation in astrocytes: roles of glutamate dehydrogenase and aminotransferases. J Neurosci Res. 2016;94:1561-1571.
12Rimmele TS, Rosenberg PA. GLT-1: the elusive presynaptic glutamate transporter. Neurochem Int. 2016;98:19-28.
13Robinson MB. Acute regulation of sodium-dependent glutamate transporters: a focus on constitutive and regulated trafficking. Handb Exp Pharmacol. 2006;175:251-275.
14Robinson RB, Jackson JG. Astroglial glutamate transporters coordinate excitatory signaling and brain energetics. Neurochem Int. 2016;98:56-71.
15Rose CR, Ziemens D, Untiet V, Fahlke C. Molecular and cellular physiology of sodium-dependent glutamate transporters. Brain Res Bull. 2018;136:3-16.
16Papouin T, Oliet SH. Organization, control, and function of extrasynaptic NMDA Receptors. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130601.
17Billups D, Marx MC, Mela I, Billups B. Inducible presynaptic glutamine transport supports glutamatergic transmission at the calyx of Held synapse. J Neurosci. 2013;33:17429-17434.
18Marx MC, Billups D, Billups B. Maintaining the presynaptic glutamate supply for excitatory neurotransmission. J Neurosci Res.2015;93:1031-1044.
19Nissen-Meyer LS, Chaudhry FA. Protein kinase C phosphorylates the system N glutamine transporter SN1 (SLC38a3) and regulates its membrane trafficking and degradation. Front Endocrinol (Lausanne). 2013;4:138.
20Olsen GM, Sonnewald U. Glutamate: where does it come from and where does it go? Neurochem Int. 2015;88:47-52.
21Schousboe A, Bak LK, Waagepetersen HS. Astrocytic control of biosynthesis and turnover of the neurotransmitters glutamate and GABA. Front Endocrinol (Lausanne). 2013;4:102.
22Schousboe A, Scafidi S, Bak LK, Waagepetersen HS, McKenna MC. Glutamate metabolism in the brain focusing on astrocytes. Adv Neurobiol. 2014;11:13-30.
23Waagepetersen HS, Qu H, Sonnewald U, Shimamoto K, Schousboe A. Role of glutamine and neuronal glutamate uptake in glutamate homeostasis and synthesis during vesicular release in cultured glutamatergic neurons. Neurochem Int. 2005;47:92-102.
24Walls AB, Waagepetersen HS, Bak LK, Schousboe A, Sonnewald U. The glutamine-glutamate/GABA cycle: function, regional differences in glutamate and GABA production and effects of interference with GABA metabolism. Neurochem Res. 2015;40:402-409.
25Bak LK, Schousboe A, Waagepetersen. The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem. 2006;98:641-653.
26Cooper AJ, Jeitner TM. Central role of glutamate metabolism in the maintenance of nitrogen homeostasis in normal and hyperammonemic brain. Biomolecules. 2016. doi: 10.3390/biom6020016.
27Hertz L. Glutamate, a neurotransmitter - and so much more. A synopsis of Wierzba III. Neurochem Int. 2006;48:416-425.
28Jayakumar AR, Norenberg MD. Glutamine synthetase: role in neurological disorders. Adv Neurobiol. 2016;13:327-350.
29Rose CF, Verkhratsky A, Parpura V. Astrocyte glutamine synthetase: pivotal in health and disease. Biochem Soc Trans. 2013;41:1518-1524.
30Verkhratsky A, Steardo L, Peng L, Parpura V. Astroglia, glutamatergic transmission and psychiatric disorders. Adv Neurobiol. 2016;13:307-326.
31Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm. 2014;121:799-817.
32Zorec R, Parpura V, Verkhratsky A. Astroglial vesicular trafficking in neurodegenerative diseases. Neurochem Res. 2017;42:905-917.
33Owens DF, Kriegstein AR. Developmental neurotransmitters? Neuron. 2002;36:989-991.
34Owens DF, Kriegstein AR. Is there more to GABA than synaptic inhibition? Nat Rev Neurosci. 2002;3:715-727.
35Alléne C, Cattani A, Ackman JB, et al. Sequential generation of two distinct synapse-driven network patterns in developing neocortex. J Neurosci. 2008;28:12851-12863.
36Ben-Ari Y. Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci. 2002;3:728-239.
37Huang ZJ. Activity-dependent development of inhibitory synapses and innervation pattern: role of GABA signalling and beyond. J Physiol. 2009;587:1881-1888.
38Luhmann HJ, Kirischuk S, Sinning A, Kilb W. Early GABAergic circuitry in the cerebral cortex. Curr Opin Neurobiol. 2014;26:72-78.
39Sonnewald U. Glutamate synthesis has to be matched by its degradation - where do all the carbons go? J Neurochem. 2014;131;399-406.
40Kreis R, Hofmann L, Kuhlmann B, Boesch C, Bossi E, Hüppi. Brain metabolite composition during early human brain development as measured by quantitative in vivo [1] H magnetic resonance spectroscopy. Magn Reson Med. 2002;48:949-958.
41Hack N, Balázs R. Selective stimulation of excitatory amino acid receptor subtypes and the survival of granule cells in culture: effect of quisqualate and AMPA. Neurochem Int. 1994;25:235-241.
42Yano S, Tokumitsu H, Soderling TR. Calcium promotes cell survival through CaM-k kinase activation of the protein-kinase-β pathway. Nature. 1998;396:584-587.
43Nedergaard M, Verkhratsky A. Artifact versus reality - how astrocytes contribute to synaptic events? Glia. 2012;60:1013-1023.
44Verkhratsky A, Nedergaard M. Why are astrocytes important. Neurochem Res. 2015;40:389-401.
45Verkhratsky A, Nedergaard M. Astroglia cradle in the life of the synapse. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130595.
46Bayraktar OA, Fuentealba LC, Alvarez-Buylla A, Rowitch DH. Astrocyte development and heterogeneticy. Cold Spring Harb Perspect Biol. 2014;7:a020362.
47Krencik R, van Asperen JV, Ullian EM. Human astrocytes are distinct contributors to the complexity of synaptic function. Brain Res Bull. 2017;129:66-73.
48Mangia S, Giove F, Dinuzzo M. Metabolic pathways and activity-dependent modulation of glutamate concentration in the human brain. Neurochem Res. 2012;37:2554-2561.
49Anlauf E, Derouiche A. Glutamine synthetase as an astrocytic marker: its cell type and vesicle localization. Front Endocrinol (Lausanne). 2013;4:144.
50Wang Y, Kudoh J, Kubota R, Asakawa S, Minoshima S, Shimizu N. Chromosomal mapping of a family of human glutamine synthetase genes: functional gene (GLUL) on 1 q25, pseudogene (GLULP) on 9p13, and three related genes (GLULL1, GLULL2, GLULL3) on 5q33, 11p15, and 11q24. Genomics. 1996;37:195-199.
51Cooper AJ, Vergara F, Duffy TE. Cerebral glutamine synthetase. In: Hertz L, Kvamme E, McGeer EF, Schousboe A, eds. Glutamine, Glutamate, and GABA in the Central Nervous System. New York: Alan R. Liss Inc. 1983:77-93.
52Öz G, Berkich DA, Henry PG, et al. Neuroglial metabolism in the awake rat brain: CO 2 fixation increases with brain activity. J Neurosci. 2004;24:11273-11279.
53Spanaki C, Zaganas I, Kounooupa Z, Plaitakis A. The complex regulation of Human glud1 and glud2 glutamate dehydrogenases and its implications in nerve tissue biology. Neurochem Int. 2012;61:470-481.
54Calvetti D, Somersalo E. Quantitative in silico analysis of neurotransmitter pathways under steady state conditions. Front Endocrinol (Lausanne). 2013;4:137.
55Bixel MG, Shimomura Y, Hutson SM, Hamprecht B. Distribution of key enzymes of branched-chain amino acid metabolism in glial and neuronal cells in culture. J Histochem Cytochem. 2001;49:407-418.
56Cole JT, Sweatt AJ, Hutson SM. Expression of mitochondrial branched-chain aminotransferase and α-keto-acid dehydrogenase in rat brain: implications for neurotransmitter metabolism. Front Neuroanat. 2012;6:18.
57Garcia-Espinosa MA, Wallin R, Hutson SM, Sweatt A. Widespread neuronal expression of branched-chain aminotransferase in the CNS: implications for leucine/glutamate metabolism and for signaling by amino acids. J Neurochem. 2007;100:1458-1468.
58Hutson SM, Berkich D, Drown P, Xu B, Aschner M, LaNoue KF. Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism. J Neurochem. 1998;71:863-874.
59Guitart K, Loers G, Schachner M, Kleene R. Prion protein regulates glutathione metabolism and neural glutamate and cysteine uptake via excitatory amino acid transporter 3. J Neurochem. 2015;133:558-571.
60Van Der Werf P, Orlowski M, Meister A. Enzymatic conversion of 5-oxo-L-proline (L-pyrrolidone carboxylate) to L-glutamate coupled with cleavage of adenosine triphosphate to adenosine diphosphate, a reaction in the γ-glutamyl cycle. Proc Natl Acad Sci U S A. 1971;68:2982-2985.
61Kumar A, Bachhawat AK. Pyroglutamic acid: throwing light on a lightly studied metabolite. Curr Sci. 2012;102:288-297.
62Bergersen LH, Gundersen V. Morphological evidence for vesicular glutamate release from astrocytes. Neurocience. 2009;158:260-265.
63Bezzi P, Gundersen V, Galbete JL, et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci. 2004;7:613-620.
64Cheung G, Chever O, Rouach N. Connexons and pannexons: newcomers in neurophysiology. Front Cell Neurosci. 2014;8:348.
65Mongin AA. Volume-regulated anion channel-a frenemy within the brain. Pflugers Arch. 2016;468:421-441.
66Montero TD, Orellana JA. Hemichannels: new pathways for gliotransmitter release. Neuroscience. 2015;286:45-59.
67Orellana JA, Stehberg J. Hemichannels: new roles in astroglial function. Front Physiol. 2014;5:193.
68Parpura V, Scemes E, Spray DC. Mechanisms of glutamate release from astrocytes: gap junction "hemichannels," purinergic receptors and exocytotic release. Neurochem Int. 2004;45:259-264.
69Bitanihirwe BK, Mauney SA, Woo TU. Weaving a net of neurobiological mechanisms in schizophrenia and unraveling the underlying pathophysiology. Biol Psychiatry. 2016;80:589-598.
70Bozzi Y, Casarosa S, Caleo M. Epilepsy as a neurodevelopmental disorder. Front Psychiatry. 2012;3:19.
71Bruno V, Caraci F, Copani A, Matrisciano F, Nicoletti F, Battaglia G. The impact of metabotropic glutamate receptors into active neurodegenerative processes: a "dark side" in the development of new symptomatic treatments for neurologic and psychiatric disorders. Neuropharmacology. 2017;115:180-192.
72Bunner KD, Rebec GV. Corticostriatal dysfunction in Huntington's Disease: the basics. Front Hum Neurosci. 2016;10:317.
73Dorsett CR, McGuire JL, DePasquale EA, Gardner AE, Floyd CL, McCullumsmith RE. Glutamate neurotransmission in rodent models of traumatic brain injury. J Neurotrauma. 2017;34:263-272.
74Field JR, Walker AG, Conn PJ. Targeting glutamate synapses in schizophrenia. Trends Mol Med. 2011;17:689-698.
75Khundakar AA, Thomas AJ. Neuropathology of depression in Alzheimer's disease: current knowledge and the potential for new treatments. J Alzheimers Dis. 2015;44:27-41.
76Martin LJ, Chang Q. Inhibitory synaptic regulation of motoneurons: a new target of disease mechanisms in amyotrophic lateral sclerosis. Mol Neurobiol. 2012;45:30-42.
77Mechawar N, Savitz J. Neuropathology of mood disorders: do we see the stigmata of inflammation? Transl Psychiatry. 2016;6:e946.
78Sanganalmath SK, Gopal P, Parker JR, Downs RK, Parker JC Jr, Dawn B. Global cerebral ischemia due to circulatory arrest: insights into cellular pathophysiology and diagnostic modalities. Mol Cell Biochem. 2017;426:111-127.
79Tarazi FI, Sahli ZT, Wolny M, Mousa SA. Emerging therapies for Parkinson's disease: from bench to bedside. Pharmacol Ther. 2014;144:123-133.
80Tsai S, Chen P, Calkins MJ, Wu S, Kuo Y. Exercise counteracts aging-related memory impairment: a potential role for the astrocytic metabolic shuttle. Front Aging Neurosci. 2016;8:57.
81Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 1999;22:208-215.
82Dallé G, Chever O, Rouach N. How do astrocytes shape synaptic transmission? Insights from electrophysiology. Front Cell Neurosci. 2013;7:159.
83Papouin T, Dunphy J, Tolman M, Foley JC, Haydon PG. Astrocytic control of synaptic function. Philos Trans R Soc Lond B Biol Sci. 2017. doi: 10.1098/rstb.2016.0154.
84Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 2009;32:421-431.
85Pérez-Alvarez A, Araque A. Astrocyte-neuron interaction at tripartite synapses. Curr Drug Targets. 2013;14:1220-1224.
86Carmignoto G, Fellin T. Glutamate release from astrocytes as a non-synaptic mechanisms for neuronal synchronization in the hippocampus. J Physiol Paris. 2006;99:98-102.
87Fellin T, Carmignoto G. Neuron-to-astrocyte signalling in the brain represents a distinct multifunctional unit. J Physiol. 2004;559:3-15.
88Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004;43:729-743.
89Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev. 2006;86:1009-1031.
90Hollman M, Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci. 1994;17:31-108.
91Conn PJ, Pin JP. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. 1997;37:205-237.
92Pin JP, Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology. 1995;34:1-26.
93Anderson MA, Ao Y, Sofroniew MV. Heterogeneity of reactive astrocytes. Neurosci Lett. 2014;565:23-29.
94Ben Haim L, Rowitch DH. Functional diversity of astrocytes in neural circuit regulation. Nat Rev Neurosci. 2017;18:31-41.
95Fellin T, Sul JY, D'Ascenzo M, Takano H, Pascual O, Haydon PG. Bidirectional astrocyte-neuron communication: the many roles of glutamate and ATP. Novartis Found Symp. 2006;276:208-217.
96Höft S, Griemsmann S, Seifert G, Steinhäuser C. Heterogeneity in expression of functional ionotropic glutamate and GABA receptors in astrocytes across brain regions: insights from the thalamus. Philos Trans R Soc Lond B Biol Sci. 2014; 369:20130602.
97Hu X, Yuan Y, Wang D, Su Z. Heterogeneous astrocytes: active players in CNS. Brain Res Bull. 2016;125:1-18.
98Olude MA, Mustapha OA, Aderounmu OA, Olopade JO, Ihunwo AO. Astrocyte morphology, heterogeneity, and density in the developing african giant rat (Cricetomys gambianus). Front Neuroanat. 2015;9:67.
99Schitine C, Nogaroli L, Costa MR, Hedin-Pereira C. Astrocyte heterogeneity in the brain: from development to disease. Front Cell Neurosci. 2015;9:76.
100Tyzack G, Lakatos A, Patani R. Human stem cell-derived astrocytes: specification and relevance for neurological disorders. Curr Stem Cell Rep. 2016;2:236-247.
101Barres BA, Koroshetz WJ, Chun LL, Corey DP. Ion channel expression by white matter glia: type-1 astrocyte. Neuron. 1990;5:527-544.
102McCarthy KD, Salm AK. Pharmacologically-distinct subsets of astroglia can be identified by their calcium response to neurogands. Neuroscience. 1991;41:325-333
103Salm AK, McCarthy KD. Norepinephrine-evoked calcium transients in cultured cerebral type 1 astroglia. Glia. 1990;3:529-538.
104Golovina VA, Blaustein MP. Unloading and refilling of two classes of spatially resolved endoplasmic reticulum Ca(2+) stores in astrocytes. Glia. 2000;31:15-28.
105Scemes E. Components of astrocytic intercellular calcium signaling. Mol Neurobiol. 2000;22:167-179.
106Guthrie PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB. ATP released from astrocytes mediates glial calcium waves. J Neurosci. 1999;19:520-528.
107Zanotti S, Charles A. Extracellular calcium sensing by glial cells: low extracellular calcium induces intracellular calcium release and intercellular signaling. J Neurochem. 1997;69:594-602.
108Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science. 1990;247:470-473.
109Kang J, Jiang L, Goldman SA, Nedergaard M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat Neurosci. 1998;1:683-692.
110Parri HR, Gould TM, Crunelli V. Spontaneous astrocytic Ca 2+ oscillations in situ drive NMDAR-mediated neuronal excitation. Nat Neurosci. 2001;4:803-812.
111Bonansco C, Couve A, Perea G, Ferradas CA, Roncagliolo M, Fuenzalida M. Glutamate released spontaneously from astrocytes sets the threshold for synaptic plasticity. Eur J Neurosci. 2011;33:1483-9142.
112Sontheimer H. Astrocytes, as well as neurons, express a diversity of ion channels. Can J Physiol Pharmacol. 1882;70:S223-238.
113Hwang EM, Kim E, Yarishkin O, et al. A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes. Nat Commun. 2014;5:3227.
114Ryoo K, Park JY. Two-pore domain potassium channels in astrocytes. Exp Neurobiol. 2016;25:222-232.
115Woo DH, Han KS, Shim JW, et al. TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell. 2012;151:25-40.
116Volterra A, Meldolesi J. Asrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci. 2005;6:626-640.
117Nakanishi S, Nakajima Y, Nomura A, et al. Functions and roles of glutamate receptors in synaptic transmission and plasticity. Cold Spring Harb Symp Quant Biol. 1996;61:67-75..
118Crépel V, Mulle C. Physiopathology of kainate receptors in epilepsy. Curr Opin Pharmacol. 2015;20:83-88.
119Endele S, Rosenberger G, Geider K, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010;42:1021-1026.
120Niciu MJ, Ionescu DF, Richards EM, Zarate CA Jr. Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder. J Neural Transm (Vienna). 2014;121:907-924.
121Panzer JA, Gleichman AJ, Lynch DR. Glutamatergic autoencephalitides: an emerging field. J Neural Transm (Vienna). 2014;121:957-968.
122Paula-Lima AC, Brito-Moreira J, Ferreira ST. Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's Disease. J Neurochem. 2013;126:191-202.
123Soto D, Altafaj X, Sindreu C, Bayés A. Glutamate receptor mutations in psychiatric and neurodevelopmental disorders. Commun Integr Biol. 2014;7:e27887.
124Yuan H, Low CM, Moody OA, Jenkins A, Traynelis SF. Ionotropic GABA and glutamate receptor mutations and human neurologic diseases. Mol Pharmacol. 2015;88:203-217.
125Lee K, Goodman L, Fourie C, Schenk S, Leitch B, Montgomery JM. AMPA receptors as therapeutic targets for neurological disorders. Adv Protein Chem Struct Biol. 2016;103:203-261.
126Arai Y, Mizuguchi M, Takashima S. Developmental changes of glutamate receptors in the rat cerebral cortex and hippocampus. Anat Embryol (Berl). 1997;195:65-70.
127Herlenius E, Lagercrantz H. Development of neurotransmitter systems during critical periods. Exp Neurol. 2004;190:S8-S21.
128Herlenius E, Lagercrantz H. Neurotransmitters and neuromodulators during early human development. Early Hum Dev. 2001;65:21-37.
129Makino H, Malinow R. AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron. 2009;64:381-390.
130Wang Z, Edwards JG, Riley N, et al. Myosin Vb mobilizes recycling endosomes and AMPA receptors for postsynaptic plasticity. Cell. 2008;135:535-548.
131Collingridge GL, Isaac JT, Wang YT. Receptor trafficking and synaptic plasticity. Nat Rev Neurosci. 2004;5:952-962.
132Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002;25:103-126.
133Hanley JG. Subunit-specific trafficking mechanisms regulating the synaptic expression of Ca(2+)-permeable AMPA receptors. Semin Cell Dev Biol. 2014;27:14-22.
134Cull-Candy S, Kelly L, Farrant M. Regulation of Ca 2+ -permeable AMPA receptors: synaptic plasticity and beyond. Curr Opin Neurobiol. 2006;16:288-297.
135Traynelis SF, Wollmuth LP, McBain CJ, et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 2010;62:405-496.
136Liu SJ, Savtchouk I. Ca 2+ permeable AMPA receptors switch allegiances: mechanisms and consequences. J Physiol. 2012;590:13-20.
137Sanz-Clemente A, Nicoll RA, Roche KW. Diversity in NMDA receptor composition: many regulators, many consequences. Neuroscientist. 2013;19:62-75.
138Paoletti P. Molecular basis of NMDA receptor functional diversity. Eur J Neurosci. 2011;33:1351-1365.
139Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013;14:383-400.
140Paupard MC, Friedman LK, Zukin RS. Developmental regulation and cell-specific expression of N-methyl-D-aspartate receptor splice variants in rat hippocampus. Neuroscience. 1997;79:399-409.
141Pérez-Otaño I, Larsen RS, Wesseling JF. Emerging roles of GluN3-containing NMDA receptors in the CNS. Nat Rev Neurosci. 2016;17:623-635.
142Egebjerg J, Bettler B, Hermans-Borgmeyer I, Heinemann S. Cloning of a cDNA for a glutamate receptor subunit activated by kainate but not AMPA. Nature. 1991;351:745-748.
143Schiffer HH, Swanson GT, Heinemann SF. Rat GluR7 and a carboxy-terminal splice variant, GluR7b, are functional kainate receptor subunits with a low sensitivity to glutamate. Neuron. 1997;19:1141-1146.
144Herb A, Burnashev N, Werner P, Sakmann B, Wisden W, Seeburg PH. The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits. Neuron. 1992;8:775-785.
145Werner P, Voigt M, Keinanen K, Wisden W, Seeburg PH. Cloning of a putative high-affinity kainate receptor expressed predominately in hippocampal CA3 cells. Nature. 1991;351:742-744.
146Fletcher EJ, Lodge D. New developments in the molecular pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate and kainate receptors. Pharmacol Ther. 1996;70:65-89.
147Ruiz A, Sachidhanandam S, Utvik JK, Coussen F, Mulle C. Distinct subunits in heteromeric kainate receptors mediate ionotropic and metobotropic function at hippocampal mossy fiber synapses. J Neurosci. 2005;25:11710-11718.
148Vargas JR, Takahashi DK, Thomson KE, Wilcox KS. The expression of kainate receptor subunits in hippocampal astrocytes following experimentally induced status epilepticus. J Neuropathol Exp Neurol. 2013;72:919-932.
149Bernardinelli Y, Magistretti PJ, Chatton JY. Astrocytes generate Na + -mediated metabolic waves. Proc Natl Acad Sci U S A. 2004;101:14937-14942.
150Peller L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A. 1994;91:10625-10629.
151Fellin T, Gomez-Gonzalo M, Gobbo S, Carmignoto G, Haydon PG. Astrocytic glutamate is not necessary for the generation of epileptiform neuronal activity in hippocampal slices. J Neurosci. 2006;26:9312-9322.
152Tian GF, Azmi H, Takano T, et al. An astrocytic basis of epilepsy. Nat Med. 2005;11:973-981.
153Jeong H, Ji K, Min K, et al. Astrogliosis is a possible player in preventing delayed neuronal death. Mol Cells. 2014;37:345-355.
154Casse F, Bardou I, Danglio L, et al. Glutamate controls tPA recycling by astrocytes, which in turn influences glutamatergic signals. J Neurosci. 2012;32:516-519.
155Mothet JP, Pollegioni L, Ouanounou G, Martineau M, Fossier P, Baux G. Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine. Proc Natl Acad Sci U S A. 2005;102:5606-5611.
156Angulo M, Kozlov AS, Charpak S, Audinat E. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci. 2005;24:6920-6927.
157Hepp R, Hay YA, Aguado C, et al. Glutamate receptors of the delta family are widely expressed in the adult brain. Brain Struct Funct. 2014;220:2797-2815.
158Gao J, Maison SF, Wu X, et al. Orphan glutamate receptor 1 subunit required for high-frequency hearing. Mol Cell Biol. 2007;27:4500-4512.
159Mandolesi G, Cesa R, Autuori E, Strata P. An orphan ionotropic glutamate receptor: the delta2 subunit. Neuroscience. 2009;158:67-77.
160Schmid SM, Hollmann M. Bridging the synaptic cleft: lessons from orphan glutamate receptors. Sci Signal. 2010;3:pe28.
161Yuzaki M, Aricescu R. A GluD coming-of-age story. Trends Neurosci. 2017;40:138-150.
162Orth A, Tapken D, Hollmann M. The delta subfamily of glutamate receptors: characterization of receptor chimeras and mutants. Eur J Neurosci. 2013;37:1620-1630.
163Konno K, Matsuda K, Nakamoto C, et al. Enriched expression of GluD1 in higher brain regions and its involvement in parallel fiber-interneuron synapse formation in the cerebellum. J Neurosci. 2014;34:7412-7424.
164Ryu K, Yokoyama M, Yamashita M, Hirano T. Induction of excitatory and inhibitory presynaptic differentiation by GluD1. Biochem Biophys Res Commun. 2012;417:157-161.
165Ady V, Perroy J, Tricoire L, et al. Type 1 metabotropic glutamate receptors (mGlu1) trigger the gating of GluD2 delta glutamate receptors. EMBO Rep. 2014;15:103-109.
166Pin JP, Galvez T, Prezeau L. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther. 2003;98:325-354.
167Ribeiro FM, Vieira LB, Pires RGW, Olmo RP. Metabotropic glutamate receptors and neurodegenerative diseases. Pharmacol Res. 2017;115:179-191.
168Alagarsamy S, Marino MJ, Rouse ST, Gereau RWT, Heinemann SF, Conn PJ. Activation of NMDA receptors reverse desensitization of mGluR5 in native and recombinant systems. Nat Neurosci. 1999;2:234-240.
169Heidinger V, Manzerra P, Wang XQ, et al. Metabotropic glutamate receptor 1-induced upregulation of NMDA receptor current: mediation through the Pyk2/Src-family kinase pathway in cortical neurons. J Neurosci. 2002;22:5452-5461.
170Hermans E, Challiss. Structura, signaling and regulatory properties of the group 1 metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. Biochem J. 2001;359:465-484.
171Iacovelli L, Bruno V, Salvatore L, et al. Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways. J Neurochem. 2002;82:216-223.
172Lu WY, Xiong ZG, Lei S, et al. G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors. Nat Neurosci. 1999;2:331-338.
173Dehnes Y, Chaudhry FA, Ullensvang K, Lehre KP, Storm-Mathisen J, Danbolt NC. The glutamate transporter EAAT4 in rat cerebellar purkinje cells: a glutamate-gated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia. J Neurosci. 1998;18:3606-3619.
174Veruki ML, Mørkve SH, Hartveit E. Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling. Nat Neurosci. 2006;9:1388-1396.
175Takasaki C, Okada R, Mitani A, et al. Glutamate transporters regulate lesion-induced plasticity in the developing somatosensory cortex. J Neurosci. 2008;28:4995-5006.
176Thomas CG, Tian H, Diamond JS. The relative roles of diffusion and uptake in clearing synaptically released glutamate change during early postnatal development. J Neurosci. 2011;31:4743-4754.
177Petr GT, Sun Y, Frederick NM, et al. Conditional deletion of the glutamate transporter GLT-1 reveals that astrocytic GLT-1 protects against fatal epilepsy while neuronal GLT-1 contributes significantly to glutamate uptake into synaptosomes. J Neurosci. 2015;35:5187-5201.
178de Vries B, Mamsa H, Stam AH, et al. Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake. Arch Neurol. 2009;66:97-101.
179Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology. 2005;65:529-534.
180Watanabe T, Morimoto K, Hirao T, Suwaki H, Watase K, Tanaka K. Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice. Brain Res. 1999;845:92-96.
181Dallaspezia S, Mazza M, Lorenzi C, Benedetti F, Smeraldi E. A single nucleotide polymorphism in SLC1A1 gene is associated with age of onset of obsessive-compulsive disorder. Eur Psychiatry. 2014;29:301-303.
182Shugart YY, Wang Y, Samuels JF, et al. A family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder in 378 families. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:886-892.
183Murphy-Royal C, Dupuis J, Groc L, Oliet SHR. Astroglial glutamate transporters in the brain: regulating neurotransmitter homeostasis and synaptic transmission. J Neurosci Res. 2017;95:2140-2151.
184Parpura V, Verkhratsky A. The astrocyte excitability brief: from receptors to gliotransmission. Neurochem Int. 2012;61:610-621.
185Parpura V, Verkratsky A. Homeostatic function of astrocytes: Ca 2+ and Na + signalling. Transl Neurosci. 2012;3:334-344.
186Rose CR, Karus C. Two sides of the same coin: sodium homeostasis and signaling in astrocytes under physiological and pathophysiological conditions. Glia. 2013;61:1191-1205.
187Verkhratsky A, Steardo L, Parpura V, Montana V. Translational potential of astrocytes in brain distorders. Prog Neurobiol. 2016;144:188-205.
188Zorec R, Araque A, Carmignoto G, Haydon PG, Verkhratsky A, Parpura. Astroglial excitability and gliotransmission: an appraisal of Ca 2+ as a signalling route. ASN Neuro. 2012. doi: 10.1042/AN20110061.
189Barbour B. An evaluation of synapse independence. J Neurosci. 2001;21:7969-7984.
190DiGregorio DA, Nusser Z, Silver RA. Spillover of glutamate onto synaptic AMPA receptors enhances fast transmission at a cerebellar synapse. Neuron. 2002;35:521-533.
191Eulenburg V, Gomeza J. Neurotransmitter transporters expressed in glial cells as regulators of synapse function. Brain Res Rev. 2010;63:103-112.
192Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002;5:405-414.
193Humeau Y, Shaban H, Bissière S, Lüthi A. Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain. Nature. 2003;426:841-845.
194Mahan VL. Neuroprotective, neurotherapeutic, and neurometabolic effects of carbon monoxide. Med Gas Res. 2012;2:32.
195Ambegaokar SS, Kolson DL. Heme oxygenase-1 dysregulation in the brain: implications for HIV-associated neurocognitive disorders. Current HIV Research. 2014;12:174-188.
196Chen J. Heme oxygenase in neuroprotection: from mechanisms to therapeutic implications. Rev Neurosci. 2014;25:269-280.
197Lin C, Yang C, Hsiao L, Chen S, Yang C. Heme oxygenase-1 induction by carbon monoxide releasing molecule-3 suppresses interleukin-1β-mediated neuroinflammation. Front Mol Neurosci. 2017;10:387.
198FangFang, Li H, Qin T, Li M, Ma S. Thymol improves high-fat diet-induced cognitive deficits in mice via ameliorating brain insulin resistance and upregulating NRF2/HO-1 pathway. Metab. Brain Dis. 2017;32;385-393.
199Kim S, Chin YW, Cho J. Protection of cultured cortical neurons by luteolin against oxidative damage through inhibition of apoptosis and induction of heme oxygenase-1. Biol Pharm Bull. 2017;40:256-265.
200Li D, Song T, Yang L, Wang X, Yang C, Jiang Y. Neuroprotective actions of pterostilbene on hypoxic-ischemic brain damage in neonatal rats through upregulation of heme oxygenase-1. Int J Dev Neurosci. 2016;54:22-31.
201Parfenova H, Leffler CW, Basuroy S, Liu J, Fedinec AL. Antioxidant roles of heme oxygenase, carbon monoxide, and bilirubin in cerebral circulation during seizures. J Cereb Blood Flow Metab. 2012;32:1024-1034.
202Shi Y, Miao W, Teng J, Zhang L. Ginsenoside Rb1 protects the brain from damage induced by epileptic seizure via Nrf2/ARE signaling. Cell Physiol Biochem. 2018;45:212-225.
203Sutherland BA, Rahman RM, Clarkson AN, et al. Cerebral heme oxygenase 1 and 2 spatial distribution is modulated following injury from hypoxia-ischemia and middle cerebral artery occlusion in rats. Neurosci Res. 2009;65:326-334.
204Vomund S, Schäfer A, Parnham MJ, Brüne B, von Knethen A. Nrf2, the master regulator of anti-oxidative responses. Int J Mol Sci. 2017. doi: 10.3390/ijms18122772.
205Qiao L, Zhang N, Huang J, Yang X. Carbon monoxide as a promising molecule to promote nerve regeneration after traumatic brain injury. Med Gas Res. 2017;7:45-47.
206Ryter SW, Choi AMK. Carbon monoxide: present and future indications for a medical gas. Korean J Intern Med. 2013;28:123-140.
207Horvat A, Vardjan N, Zorec R. Targeting astrocytes for treating neurological disorders: Carbon monoxide and noradrenaline-induced increase in lactate. Curr Pharm Des. 2017;23:4969-4978.
208Che X, Fang Y, Si X, et al. The role of gaseous molecules in traumatic brain injury: An updated review. Front Neurosci. 2018;12:392.
209Choi SY, Kim KJ, Song JH, Lee BY. Ginsenoside Rg5 revents apoptosis by modulating heme-oxygenase-1/nuclear factor E2-related factor 2 signaling and alters the expression of cognitive impairment-associated genes in thermal stress-exposed HT22 cells. J Gensing Res. 2018;42:225-228.
210Klemz R, Reischl S, Wallach T, et al. Reciprocal regulation of carbon monoxide metabolism and the circadian clock. Nat Struct Mol Biol. 2017;24:15-22.
211Morroni F, Sita G, Graziosi A, et al. Neuroprotective Effect of Caffeic Acid Phenethyl Ester in a mouse model of Alzhemier's Disease involves Nrf2/HO-1 pathway. Aging Dis. 2018;9:605-622.
212Nitti M, Piras S, Brondolo L Marinari UM, Pronzato MA, Furfaro AL. Heme oxygenase 1 in the nervous system: Does it favor neuronal cell survival or induce neurodegeneration? Int J Mol Sci. 2018. doi: 10.3390/ijms19082260.
213Queiroga CS, Vercelli A, Vieira HL. Carbon monoxide and the CNS: challenges and achievements. Br J Pharmacol. 2015;172:1533-1545.
214Schipper HM. Heme oxygenase expression in human central nervous system disorders. Ree Radic Biol Med. 2004;37:1995-2011.
215Shibahara S. The heme oxygenase dilemma in cellular homeostasis: new insights for the feedback regulation of heme catabolism. Tohoku J Exp Med. 2003;200:167-186.
216Tulsulkar J, Ward A, Shah ZA. HO1 and Wnt expression is independently regulated in female mice brains following permanent ischemic brain injury. Brain Res. 2017;1662:1-6.
217Chance B, Williams GR. Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. J Biol Chem. 1955;217:383-393.
218Hüttemann M, Lee I, Pecinova A, Pecina P, Przyklenk K, Doan JW. Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease. J Bioenerg Biomembr. 2008;40:445-456.
219Saa A, Siqueira KM. Modeling the ATP production in mitochondria. Bull Math Biol. 2013;75:1636-1651.
220Oberheim NA, Takano T, Han X, et al. Uniquely hominid features of adult human astrocytes. J Neurosci. 2009;29:3276-3287.
221Jackson JG, Robinson MB. Regulation of mitochondrial dynamics in astrocytes: mechanisms, consequences, and unknowns. Glia. 2018;66:1213-1234.
222Jackson JG, Robinson MB. Reciprocal regulation of mitochondrial dynamics and calcium signaling in astrocyte processes. J Neurosci. 2015;35:15199-15213.
223Jackson JG, O'donnell JC, Takano H, Coulter DA, Robinson MB. Neuronal activity and glutamate uptake decrease mitochondrial mobility in astrocytes and position mitochondria near glutamate transporters. J Neurosci. 2014;34:1613-1624.
224O'Donnell JC, Jackson JG, Robinson MG. Transient oxygen/glucose deprivation causes a delayed loss of mitochondria and increases spontaneous calcium signaling in astrocytic processes. J Neurosci. 2016;36:7109-7127.
225Rinholm JE, Vervaeke K, Tadross MR, et al. Movement and structure of mitochondria in oligodendrocytes and their myelin sheaths. Glia. 2016;64:810-825.
226Stephen TL, Higgs NF, Sheehan DF, el al. Miro1 regulates activity-driven positioning of mitochondria within astrocytic processes apposed to synapses to regulate intracellular calcium signaling. J Neurosci. 2015;35;15996-16011.
227Stephen TL, Gupta-Agarwal S, Kitter JT. Mitochondrial dynamics in astrocytes. Biochem Soc Trans. 2014;42:1302-1310.
228Berridge MV, McConnell MJ, Grasso C, Bajzikova M, Kovarova J, Neuzil J. Horizontal transfer of mitochondria between mammalian cells: beyond co-culture approaches. Curr Opin Genet Dev. 2016;38:75-82.
229Frederick RL, Shaw JM. Moving mitochondria: establishing distribution of an essential organelle. Traffic. 2007;8:1668-1675.
230MacAskill AF, Atkin TA, Kittler JT. Mitochondrial trafficking and the provision of energy and calcium buffering at excitatory synapses. Eur J Neurosci. 2010;32:231-240.
231Misko A, Jiang S, Wegorzewska I, Milbrandt J, Balch RH. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the miro/milton Complex. J Neurosci. 2010;30:4232-4240.
232Schwarz TL. Mitochondrial trafficking in neurons. Cold Spring Harb Perspect Biol. 2013. doi: 10.1101/cshperspect.a011304.
233Kirischuk S, Kettenmann H, Verkhratsky A. Na + /Ca 2+ exchanger modulates kainate-triggered Ca 2+ signaling in bergmann glial cells in situ. FASEB J. 1997;11:566-572.
234Pellerin L, Magistretti PJ. Glutamate uptake stimulates Na + , K + -ATPase activity in astrocytes via activation of a distinct subunit highly sensitive to ouabain. J Neurochem. 1997;69:2132-2137.
235Rojas H, Colina C, Ramos M, et al. Sodium-calcium exchanger modulates the L-glutamate Ca(i) (2+) signalling in type-1 cerebellar astrocytes. Adv Exp Med Biol. 2013;961:267-274.
236Zerangue N, Kavanaught MP. Flux coupling in a neuronal glutamate transporter. Nature. 1996;383:634-637.
237Benjamin Kacerovsky J, Murai KK. Stargazing: monitoring subcellular dynamics of brain astrocytes. Neuroscience. 2015;45:1001-10014.
238Csordás G, Renken C, Varnai P, et al. Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol. 2006;174:915-921.
239Csordás G, Thomas AP, Hajnoczky G. Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO J. 1999;18:96-108.
240Kornmann B, Osman C, Walter P. The conserved GTPase gem1 regulates endoplasmic reticulum-mitochondria connections. Proc Natl Acad Sci U S A. 2011;108:14151-14156.
241Almeida AS, Queiroga CSF, Sousa MFQ, Alves PM, Vieira HLA. Carbon monoxide modulates apoptosis by reinforcing oxidative metabolism in astrocytes: role of Bcl-2. J Biol Chem. 2012;287:10761-10770.
242Bilban M, Haschemi A, Wegiel B, Chin BY, Wagner O, Otterbein LE. Heme oxygenase and carbon monoxide initiate homeostatic signaling. J Mol Med. 2008;86:267-279.
243Dallas ML, Scragg JL, Peers C. Inhibition of L-type Ca 2+ channels by carbon monoxide. Adv Exp Med Biol. 2009;648;89-95.
244Duckles H, Boycott HE, Al-Owais MM, et al. Heme oxygenase-1 regulates cell proliferation via carbon monoxide-mediated inhibition of T-type Ca 2+ channels. Pflügers Arch. 2014;467:415-427.
245Piantadosi CA, Carraway MS, Suliman HB. Carbon monoxide, oxidative stress, and mitochondrial permeability pore transition. Free Radic Biol Med. 2006;40:1332-1339.
246Scragg JL, Dallas ML, Wilkinson JA, Varadi G, Peers C. Carbon monoxide inhibits L-type Ca 2+ channels via redox modulation of key cysteine residues by mitochondrial reactive oxygen species. J Biol Chem. 2008;283:24412-24419.
247Oliveira SR, Queiroga CSF, Vieira HL. Mitochondria and carbon monoxide: cytoprotection and control of cell metabolism - a role for Ca 2+ ?" J Physiol. 2016;594:4131-4138.
248Lo Iacono L, Boczkowski J, Zini R, et al. A Carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species. Free Radic Biol Med. 2011;50:1556-1564.
249Queiroga CSF, Almeida AS, Vieira HLA. Carbon monoxide targeting mitochondria. Biochem Res Int. 2012;2012:749845.
250Taillé C, El-Benna J, Lanone S, Boczkowski J, Motterlini R. Mitochondrial respiratory chain and NAD(P)H oxidase are targets for the antiproliferative effect of carbon monoxide in human airway smooth muscle. J Biol Chem. 2005;280:25350-25360.
251Vieira HLA, Queiroga CSF, Alves PM. Pre-conditioning induced by carbon monoxide provides neuronal protection against apoptosis. J Neurochem. 2008;107:375-384.
252Zuekerbraun BS, Chin BY, Bilban M, et al. Carbon monoxide signals via inhibition of cytochrome C oxidase and generation of mitochondrial reactive oxygen species. FASEB J. 2007;21:1099-1106.
253Denton RM. Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta. 2009;1787:1309-1316.
254Griffiths EJ, Rutter GA. Mitochondrial calcium as a key regulator of mitochondrial ATP roduction in mammalian cells. Biochim Biophys Acta. 2009;1787:1324-1333.
255Peers C, Boyle JP, Scragg JL, et al. Diverse mechanisms underlying the regulation of ion channels by carbon monoxide. Br J Pharmacol. 2014;172:1546-1556.
256Riazantseva NV, Starikova EG, Tashireva LA, et al. Intracellular gaseous messengers, nitric oxide, carbon monoxide, and hydrogen sulfide participate in apoptosis regulation. Tsitologiia. 2012;54:105-111.
257Kim AY, Baik EJ. Glutamate dehydrogenase as a neuroprotective target against neurodegeneration. Neurochem Res. 2019;44:147-153.
258Palmieri L, Pardo B, Lasorsa FM, et al. Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. EMBO J. 2001;20:5060-5069.
259Contreras L. Role of AGC1/aralar in the metabolic synergies between neuron and glia. Neurochem Int. 2015;88:38-46.
260Kunji ERS, Robinson AJ. Coupling of proton and substrate translocation in the transport cycle of mitochondrial carriers. Curr Opin Struct Biol. 2010;20:440-447.
261Simpson PB, Russell JT. Role of mitochondrial Ca 2+ regulation in neuronal and glial cell signalling. Brain Res Brain Res Rev. 1998;26:72-81.
262Herzig S, Maundrell K, Martinou JC. Life without the mitochondrial calcium uniporter. Nat Cell Biol. 2013;15:1398-1400.
263Li A, Xi Q, Umstot ES, Bellner L, et al. Astrocyte-derived CO is a diffusible messenger that mediates glutamate-induced cerebral arteriolar dilation by activating smooth muscle cell KCa channels. Circ Res. 2008;102:234-241.
264Metea MR, Kofuji P, Newman EA. Neurovascular coupling is not mediated by potassium siphoning from glial cells. J Neurosci. 2008;27:2468-2471.
265Bélanger M, Allaman I, Magistretti J. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 2011;14:724-738.
266Falkowska A, Gutowska I, Goschorska M, Nowacki P, Chlubek D, Baranowska-Bosiacka I. Energy metabolism of the brain, including the cooperation between astrocytes and neurons, especially in the context of glycogen metabolism. Int J Mol Sci. 2015;16:25959-25981.
267Gjedde A, Marrett S, Vafaee M. Oxidative and nonoxidative metabolism of excited neurons and astrocytes. J Cereb Blood Flow Metab. 2002;22:1-14.
268Mächler P, Wyss MT, Elsayed M, et al. In vivo evidence for a lactate gradient from astrocytes to neurons. Cell Metab. 2016;23:94-102.
269Illavionava NB, Brismar H, Aperia A, Gunnarson E. Role of Na,K-ATPase α1 and α2 isoforms in the support of astrocyte glutamate uptake. PLoS One. 2014;9:e98469.
270Rose EM, Ko JC, Angflick JE, Ahmed SM, Angers S, Hampson DR. Glutamate transporter Coupling to Na,K-ATPase. J Neurosci. 2009;29:8143-8155.
271Ames A 3 rd . CNS energy metabolism as related to function. Brain Res Brain Res Rev. 2000;34:42-68.
272Astrup J, Sorensen PM, Sorensen HR. Oxygen and glucose consumption related to Na + -K + transport in canine brain. Stroke. 12:726-730.
273Gerkau NJ, Rakers C, Petzold GC, Rose CR. Differential effects of energy deprivation on intracellular sodium homeostasis in neurons and astrocytes. J Neurosci Res. 2017;95:2275-2285.
274Whittam R. The dependence of the respiration of brain cortex on active cation transport. Biochem J. 1962;82:205-212.
275Montana V, Malarkey EB, Verderio C, Matteoli M, Parpura V. Vesicular transmitter release from astrocytes. Glia. 2006;54:700-715.
276Ni Y, Malarkey EB, Parpura V. Vesicular release of glutamate mediates bidirectional signaling between astrocytes and neurons. J Neurochem. 2007;103:1273-1284.
277Ni Y, Parpura V. Dual regulation of Ca 2+ -dependent glutamate release from astrocytes: vesicular glutamate transporters and cytosolic glutamate levels. Glia. 20;57(12):1296-1305.
278Parpura V, Baker BJ, Jeras M, Zorec R. Regulated exocytosis in astrocytic signal integration. Neurochem Int. 2010;57:451-459.
279Miyata H, Silverman HS, Sollott SJ, Lakatta EG, Stern MD, Hansford RG. Measurement of mitochondrial free Ca 2+ concentration in living single rat cardiac myocytes. Am J Physiol. 1991;261:H1123-1134.
280De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature. 2011;476:336-340.
281Baughman JM, Perochchi F, Girgis HS, et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature. 2011;476:341-345.
282Celsi F, Pizzo P, Brini M, et al. Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. Biochim Biophys Acta. 2009;1787:335-344.
283McCormack JG, Halestrap AP, Denton RM. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev. 1990;70:391-425.
284Murgia M, Giorgi C, Pinton P, Rizzuto R. Controlling metabolism and cell death: at the heart of mitochondrial calcium signalling. J Mol Cell Cardiol. 2009;46:781-788.
285Takeuchi A, Kim B, Matsuoka S. The destiny of Ca 2+ released by mitochondria. J Physiol Sci. 2015;65:11-24.
286Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol. 2012;13:566-578.
287Robinson AJ, Overy C, Kunji ERS. The mechanism of transport by mitochondrial carriers based on analysis of symmetry. PNAS. 2008;105:17766-17771.
288Angulo C, Kozlov S, Charpak S, Audinat E, Anci M, Universitaria C. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci. 2004;24:6920-6927.
289Szatkowski M, Barbout B, Attwell D. Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature. 1990;348:443-446.
290Gebremedhin D, Yamaura K, Zhang C, Bylund J, Koehler RC, Harder DR. Metabotropic glutamate receptor activation enhances the activities of two types of Ca 2+ -activated K + channels in rat hippocampal astrocytes. J Neurosci. 2003;23:1678-1687.
291Kindler CH, Pietruck C, Yost CS, Sampson ER, Gray AT. Localization of the tandem pore domain K + channel TASK-1 in the rat central nervous system. Mol Brain Res. 2000;80:99-106.
292Seifert G, Henneberger C, Steinhäuser. Diversity of astrocyte potassium channels: an update. Brain Res Bull. 2018;136:26-36.
293Takumi T, Ishii T, Hori Y, et al. A novel ATP-dependent inward rectifier potassium channel expressed predominantly in glial cells. J Biol Chem. 1995;270:16339-16346.
294Zhong S, Du Y, Kiyoshi CM, et al. Electropysiological behavior of neonatal astrocytes in hippocampal stratum radiatum. Mol Brain. 2016;9:34.
295Berkich DA, Ola MS, Cole J, Sweatt AJ, Hutson SM, LaNoue KF. Mitochondrial transport proteins of the brain. J Neurosci Res. 2007;85:3367-3377.
296Del Arco A, Contreras L, Pardo B, Satrustegui J. Calcium regulation of mitochondrial carriers. Biochim Biophys Acta. 2016;1863:2413-2421
297Benesova J, Hock M, Butenko O, Prajerova I, Anderova M, Chvatal A. Quantification of astrocyte volume changes during ischemia in situ reveals two populations of astrocytes in the cortex of GFAP/EGFP mice. J Neurosci Res. 2009;87:96-111.
298Wang R, Wu L. Interaction of selective amino acid residues of K(ca) channels with carbon monoxide. Exp Biol Med (Maywood). 2003;228:474-480.
299Pereira de Ávila MA, Giusti-Paiva A, Giovani de Oliveira Nascimento C. The peripheral antinociceptive effect induced by the heme oxygenase/carbon monoxide pathway is associated with ATP-sensitive K + channels. Eur J Pharmacol. 2014;726:41-48.
300Al-Owais MM, Scragg JL, Dallas ML, et al. Carbon monoxide mediates the anti-apoptotic effects of heme oxygenase-1 in medulloblastoma DAOY cells via K + channel inhibition. J Biol Chem. 2012;287:24754-24764.
301Peers C. Ion channels as target effectors for carbon monoxide. Exp Physiol. 2011;96.9:836-839.
302Azarias G, Perreten H, Lengacher S, et al. Glutamate transport decreases mitochondrial pH and modulates oxidative metabolism in astrocytes. J Neurosci. 2011;31:3550-3559.
303Bauer DE, Jackson JG, Genda EN, Montoya MM, Yudkoff M, Robinson MB. The glutamate transporter, GLAST, participates in a macromolecular complex that supports glutamate metabolism. Neurochem. 2012;61:566-574.
304Belanger M, Allaman I, Magistretti PJ. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 2011;14:724-738.
305Benediktsson AM, Marrs GS, Tu JC, et al. Neuronal activity regulates glutamate transporter dynamics in developing astrocytes. Glia. 2012;60:175-188.
306Robinson MB, Jackson JG. Astroglial glutamate transporters coordinate excitatory signaling and brain energetics. Neurochem Int. 2016;98:56-71.
307Sun W, Shchepakin D, Kalachev LV, Kavanaugh MP. Glutamate transporter control of ambient glutamate levels. Neurochem Int. 2014;73:146-151.
308Voutsinos-Porche B, Bonvento G, Tanaka K, et al. Glial glutamate transporters mediate a functional metabolic crosstalk between neurons and astrocytes in the mouse developing cortex. Neuron. 2003;37:275-286.
309Weber B, Barros LF. The astrocyte: powerhouse and recycling center. Cold Spring Harb Perspect Biol. 2015;7: a020396.
310Bellaver B, Souza DG, Souza DO, Qincozes-Santos A. Hippocampal astrocyte cultures from adult and aged rats reproduce changes in glial functionality observed in the aging brain. Mol Neurobiol. 2017;54:2969-2985.
311Trotti D, Danbolt NC, Volterra A. Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci. 1998;19:328-334.
312Vargas MR, Johnson JA. The Nrf2-ARE cytoprotective pathway in astrocytes. Expert Rev Mol Med. 2009;11:e17.
313Wakabayashi N, Sloum SL, Skoko JJ, Shin S, Kensler TW. When NRF2 talks, who's listening? Antioxid Redox Signal. 2010;13:1649-1663.
314Akgül G, McBain CJ. Diverse roles for ionotropic glutamate receptors on inhibitory interneurons in developing and adult brain. J Physiol. 2016;594:5471-5490.
315Hadzic M, Jack A, Wahle P. Ionotropic glutamate receptors: which ones, when, and where in the mammalian neocortex. J Comp Neurol. 2017 Mar 1;525:976-1033.
316Kirchhoff F. Analysis of functional NMDA receptors in astrocytes. Methods Mol. Biol. 2017;1677:241-251.
317Rose CR, Felix L, Zeug A, Dietrich D, Reiner A, Henneberger C. Astroglial glutamate signaling and uptake in the hippocampus. Front Mol Neurosci. 2018;10:451.
318Gaynor JW, Kim DS, Arrington CB, et al. Validation of association of the apolipoprotein E å2 allele with neurodvelopmental dysfunction after cardiac surgery in neonates and infants. J Thorac Cardiovasc Surg. 2014;148:2560-2566.
319Gong JS, Kobayashi M, Hayashi H, et al. Apolipoprotein E (ApoE) isoform-dependent lipid release from astrocytes prepared from human ApoE3 and ApoE4 knock-in mice. J Biol Chem. 2002;277:29919-29926.
320Graeser AC, Boesch-Saadatmandi C, Lippmann J, et al. Nrf2-dependent gene expression is affected by the proatherogenic apoE4 genotype-studies in targeted gene replacement mice. J Mol Med (Berl). 2011;89:1027-1035.
321Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med (Berl). 2016;94:739-746.
322Omodaka K, Nishiguchi KM, Yasuda M, et al. Neuroprotective effect against axonal damage-induced retinal ganglion cell death in apolipoprotein E-deficient mice through the suppression of kainate receptor signaling. Brain Res. 2014;1586:203-212.
323Ravella K, Yang H, Gangula PR. Impairment of gastric nitrergic and NRF2 system in apolipoprotein E knockout mice. Dig Dis Sci. 2012;57:1504-1509.
324Bassani S, Valnegri P, Beretta F, Passafaro M. The GluR2 subunit of AMPA receptors: synaptic role. Neuroscience. 2009;158:55-61.
325Bennett MV, Pelligrini-Giampietro DE, Gorter JA, Aronica E, Connor JA, Zukin RS. The GluR2 hypothesis: Ca(++)-permeable AMPA receptors in delayed neurodegeneration. Cold Spring Harb Symp Quant Biol. 1996;61:373-384.
326Droste D, Seifert G, Seddar L, Jädtke O, Steinhäuser C, Lohr C. "Ca 2+ -permeable AMPA receptors in mouse olfactory bulb astrocytes. Sci Rep. 2017;7:44817.
327Wright A, Vissel B. The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain. Front Mol Neurosci. 2012;5:34.
328Clements JD, Lester RA, Tong G, Jahr CE, Westbrook GL. The time course of glutamate in the synaptic cleft. Science. 1992;258:1498-150.
329Leffler CW, Parfenova H, Fedinec Al, Basuroy S, Tcheranova D. Contribution of astrocytes and CO to a pial arteriolar dilation to glutamate in newborn pigs. 2006;291:H2897-2904.
330Taskiran D, Kutay FZ, Pogun S. Effect of carbon monoxide on dopamine and glutamate uptake and cGMP levels in rat brain. Neuropsychopharmacology. 2003;28:1176-1181.
331Parfenova H, Tcheranova D, Basuroy S, Fedinec AL, Liu J, Leffler CW. Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate. Am J Physiol Heart Circ Physiol. 2012;302:H2257-2266.
332Xi Q, Tcheranova D, Basuroy S, Parfenova H, Jaggar JH, Leffler CW. "Glutamate-induced calcium signals stimulate CO production in piglet astrocytes. Am J Physiol Heart Circ Physiol. 2011;301:H428-433.
333Chatton JY, Pellerin L, Magistretti PJ. GABA uptake into astrocytes is not associated with significant metabolic cost: implications for brain imaging of inhibitory transmission. Proc Natl Acad Sci USA. 2003;100:12456-12461.
334Liu QS, Xu Q, Arcuino G, Kang J, Nedergaard M. Astrocyte-mediated activation of neuronal kainate receptors. Proc Natl Acad Sci U S A. 2004;101:3172-3177.