Articulo 1

REVIEW
Neurointegrity and europhysiology: 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 to: Vicki L. Mahan, MD, [email protected].

orcid: 0000-0002-5284-8818 (Vicki L. Mahan)
Abstract
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 intermedi-
ates. 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 gaso-
transmitter, 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.
Key words: carbon monoxide; astrocytes; glutamate metabolism in the brain; neuroprotection by carbon monoxide; astrocyte control of
glutamate metabolism; gasotransmitters; neurotherapy; neuroprotection; GABA
doi: 10.4103/2045-9912.254639
How to cite this article: Mahan VL. Neurointegrity and europhysiology: astrocyte, glutamate, and carbon monoxide interactions. Med Gas
Res. 2019;9(1):24-45.
INTRODUCTION and amino acid metabolism via the tricarboxylic acid cycle,
Central nervous system (CNS) progenitor cells differentiate glutamate is an immediate precursor of γ-aminobutyric acid
into three main cell types – neurons, astrocytes, and oligoden- (GABA), initially excitatory and later inhibitory, and is re-
drocytes. Cell proliferation, survival, migration, differentia- quired for normal development of the brain. It acts as a trophic
tion, and apoptosis are regulated by multiple signals including factor that influences proliferation, migration, differentiation,
neurotransmitters that are critical for normal brain develop- synapse maturation, and cell death during CNS develop-
ment and function.1-7 Composed of electrically excitable neu- ment.33,34 Excitation by GABA is a result of high intracellular
ronal networks that are connected by chemical synapses, CNS concentrations of chloride and is followed by sequential
homeostasis is primarily provided by the non-externally excit- formation of GABA-releasing and glutamatergic synapses.
able astrocytes. The latter, identified by an algorithm based Giant depolarizing potentials, generated in part by excitatory
on cytological features,8 supplies neurons with glutamate, the actions of GABA, result in the generation of large oscillations
conjugate base of glutamic acid and the major neurotransmit- of intracellular calcium and activity-dependent synapse forma-
ter of the CNS. Astroglial regulation of the neurotransmitter is tion (glutamate and GABA synapses) and neuronal growth.
through uptake, release through vesicular and non-vesicular A chloride-extruding system develops later and results in the
pathways, and catabolism to intermediates9-16 and requires inhibitory effects of GABA.35-38 GABA is, thus, inhibitory in
that glutamate is adequately and constantly replenished and the developed human brain, glutamate excitatory, and GABA
that anaplerosis and cataplerosis are balanced.17-24 Directed to is required for glutamate synapse development in the CNS.
several different biochemical pathways, glutamate is important The physiologic changes noted above depend on the bio-
to glutamate-glutamine cycling. Net formation of glutamate chemical requirements of the developing brain for normal
from glucose is required for glutamatergic neuronal signaling functioning. These constantly change and evolve in all age
in the CNS, requires astrocytic pyruvate carboxylase (PC) groups. While the TCA cycle is important for glutamate
and astrocytic tricarboxylic acid (TCA) cycle activity and is synthesis in both the astrocyte and the neuron, the shuttle of
required for CNS function. Return of glutamate to neurons and glutamate from neurons to astrocytes is limited in the neona-
continued release of glutamate depend on astrocyte glutamine tal brain. This is compensated for by astrocytic anaplerosis
synthetase (GS) activity. The dynamic metabolic fluxes in via increased pyruvate carboxylation.20,24,39 Fewer astrocytes
astrocytes and cellular localization of metabolic processes are present in the newborn brain compared to the adult brain
determine metabolic formation and degradation of glutamate. and PC activity is lower. Gliogenesis occurs mainly during
Astrocyte contributions to brain function and prevention the first few weeks after birth. Glutamate levels double from
of neuropathologies are as extensive as that of neurons. week 32 gestational age and continue to increase in the first
Homeostasis of glutamate by astrocytes is considered to be year of life.40 The major role of neurotransmitters, including
of primary importance in determining normal CNS health glutamate, in neuronal differentiation, migration, and survival
and physiology.25-32 A major metabolite connecting glucose in the developing brain is mainly through facilitating the entry
24 © 2019 Medical Gas Research | Published by Wolters Kluwer - Medknow
Mahan VL. / Med Gas Res www.medgasres.com
of Ca2+ 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.43-45 Astrogenesis is
required for the majority of functional synapses – morphologic
and functional diversity occurs during development.46,47 Gluta-
mate is central to these dynamic changes and resulting clinical
outcomes – gasotransmitters may affect these diverse interac-
tions 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 Figure 1: Glutamate-glutamine-GABA cycle.
of carbon monoxide on astrocyte homeostasis of glutamate. Note: Astrocyte and neuron roles in metabolic processes and the release and
reuptake of neurotransmitters. Gln: Glutamine; GAD: glutamate decarboxylase;
METABOLISM OF GLUTAMATE IN THE ASTROCYTE AND GABA-T: GABA transaminase; GDH: glutamate dehydrogenase; SSADH: succinic
semialdehyde dehydrogenase; AST: aspartate aminotransferase; PAG: phosphate-
NEURON activated glutaminase; GABA: γ-aminobutyric acid.
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 tant for removal of ammonia (NH3) and is a major route for
within the brain as the blood-brain-barrier effectively excludes removal of glutamate from the CNS.
most of the blood-borne glutamate and there is net removal of Net synthesis of the non-toxic glutamine, precursor of
glutamine. The neurotransmitter is not uniformly distributed glutamate and GABA, occurs only in astrocytes and requires
and, potentially neurotoxic, low extracellular fluid concentra- cellular compartmentalization of GS and PC.22 Catalyzed
tions of glutamate are necessary to avoid excitotoxity. The by GS, L-glutamate combines with ammonia and adenosine
required levels for normal function vary in different regions triphosphatase (ATP) to form L-glutamine, adenosine diphos-
of the brain and during different times of life. Concentration phate (ADP), and phosphate:
influences its dual role as neurotransmitter and energy source. L-Glutamate + NH3 + ATP ↔ L-Glutamine + ADP + Pi.
Glutamine is a major source of CNS glutamate via the
A concentration gradient of CNS glutamate, vesicles > cytosol/
glutaminase (present in neurons and astrocytes) reaction51:
mitochondria > extracellular fluid, is a result of the effective-
L-Glutamine + H2O → L-Glutamate + NH3.
ness of astrocyte glutamate synthesis, glutamate catabolism,
The glutamate-glutamine cycle loses intermediates to other
and glutamate transporters. De novo synthesis of TCA cycle
pathways and de novo synthesis of glutamine in astrocytes is
intermediates from glucose catalyzed by PC results in the
needed to continue its operation. Anaplerosis is mediated by
formation of oxaloacetate, essential for the de novo synthesis
PC and ranges from 6 to 35% of the rate of the TCA cycle
of glutamate and the glutamine that is transferred from astro-
which meets this requirement52 with the resulting oxaloacetate
cytes to neurons to maintain the pool of glutamate. Complete
entering the Krebs cycle:
and/or partial pyruvate recycling via oxidation of glutamate
Pyruvate + CO2 + ATP → Oxaloacetate + ADP + Pi.
is important in balancing the PC anapleurotic reaction. These
processes are dynamic and change with brain activity and the Glutamate/α-ketoglutarate-linked aminotransferases coupled
release of K+ by synaptic terminals during depolarization.39,48 to the glutamate dehydrogenase reaction
Metabolism of glutamate is affected via the GS reaction, Catabolism of glutamate to carbon dioxide (CO2) requires ac-
glutamate/α-ketoglutarate-linked aminotransferases coupled to cess to the TCA cycle and pyruvate recycling. The coupling
the glutamate dehydrogenase (GDH) reaction, decarboxylation of an aminotransferase reaction to the GDH reaction gener-
to GABA, and glutathione (GSH). ates ammonia or incorporates ammonia into an amino acid.
The TCA cycle-derived α-ketoglutarate provides the carbon-
Glutamine synthetase reaction skeleton for glutamate and maintains glutamate nitrogen levels.
The glutamate-glutamine cycle (Figure 1) describes the trans- The glutamate-glutamine cycle is coupled to the
fer of glutamate from neurons to astrocytes and subsequent α-ketoglutarate cycle via the mitochondrial GDH:
return of glutamine from astrocytes to neurons. There is not a L-Glutamate + NAD(P)+ + H2O ↔ α-Ketoglutarate + NH4+
stoichiometric relationship between glutamate flux out of the + NAD(P)H.
presynaptic neurons and the flux of glutamine from astrocytes Present as two isoforms in humans (GDH1 and GDH2), the
back to the presynaptic terminals. Important to the process, enzymes differ greatly with regards to allosteric regulation.53
astrocytes represent a heterogenous population of cells and GS, GDH is the major route of glutamate oxidation in astrocytes.26
an astrocyte marker.49 Three types of GS have been identified, As a co-substrate in all aminotransferase catalyzed reac-
GSI, GSII, and GSIII. Humans have the GSII type.50 Located tions, glutamate also has a major role in astrocyte amino-acid
primarily in the cytoplasm of astrocytes, human GS is impor- interconversion. α-Ketoglutarate-linked aminotransferases are
Medical Gas Research ¦ March ¦ Volume 9 ¦ Issue 1 25
important for the transport of reducing equivalents from cy- a major source of peptide-bound glutamate and is more
tosol to mitochondria. Three aminotransferases are important prevalent in astrocytes than in neurons. Uptake of cysteine
players in the conversion of glutamate to α-ketoglutarate – the is the major determinant of its production in the CNS and is
aspartate, alanine, and branched chain amino acid aminotrans- mediated by the excitatory amino acid transporter 3 and the
ferases. The first is the major enzyme responsible for produc- alanine, serine and cysteine system that transports alanine,
tion of α-ketoglutarate that can be oxidatively metabolized in serine, and cysteine.59 Synthesis requires 2 ATP-dependent
the TCA cycle to form oxaloacetate and then aspartate. steps, the first catalyzed by γ-glutamylcysteine ligase (rate
Mitochondrial aspartate aminotransferase (AAT) catalyzes limiting step) and the second by glutathione synthetase:
the following reaction: L-Glutamate + L-Cysteine + ATP → L-γ-Glutamylcysteine
L-Glutamate + Oxaloacetate ↔ L-Aspartate + + ADP + Pi
α-Ketoglutarate. L-γ-Glutamylcysteine + Glycine + ATP → GSH + ADP
The reaction proceeds readily in both directions and is im- + Pi.
portant in the TCA cycle. AAT, present in all tissues, has the Astrocytic GSH released to the interstitial space is hydro-
highest specific activity in the brain. lyzed to γ-glutamycysteine and glycine. γ-glutamycysteine
Located in the cytoplasm and requiring the cofactor is then hydrolyzed to glutamate and cysteine that are then
pyridoxal-5-phosphate, alanine aminotransferase catalyzes actively transported into neurons by excitatory amino acid
the interconversion of alanine, α-ketoglutarate, pyruvate, and transporter 3 and excitatory amino acid transporter 2.
glutamate. In the neuron,
L-Glutamate + Pyruvate → L-Alanine + α-Ketoglutarate. Other sources of astrocyte glutamate
In the astrocyte, 5-Oxoproline (5-OP), pyroglutamic acid, is ubiquitous in
L-Alanine + α-Ketoglutarate → L-Glutamate + Pyruvate. nature and is the cyclic lactam of glutamate, a reservoir of
This nitrogen shuttle requires uptake of alanine by astrocytes glutamate. It is found as a free metabolite in living cells and
and transamination of alanine in the astrocytes.54 as an N-terminal modification in antibodies, enzymes, struc-
The essential branched chain amino acids valine, leucine, tural proteins, neuronal peptides and hormones (including the
and isoleucine rapidly cross the blood-brain barrier and are accumulating peptides in Alzheimer’s disease and familial de-
taken up by astrocytes. CNS uptake requires that an equivalent mentia). The γ-glutamyl cycle describes the enzymatic forma-
amount of nitrogen exits the brain to maintain nitrogen homeo- tion of 5-OP from glutathione by γ-glutamyl cyclotransferase
stasis. Intracellular amino acid nitrogen is incorporated into and degradation of 5-OP to L-glutamate by 5-oxoprolinase.
glutamine which then moves to the extracellular compartment. 5-Oxoprolinase, a pyro-glutamic acid-cleaving enzyme, acts
In astrocytes, the mitochondrial isozyme of the branched chain on 5-OP to form L-glutamate60,61:
amino acid aminotransferase isozymes catalyzes the metabo- 5-OP + ATP + 2H2O → L-glutamate + ADP + Pi.
lism of valine, leucine and isoleucine by transamination with
α-ketoglutarate to form α-ketoisovalerate, α-ketoisocaproate, PHYSIOLOGY OF GLUTAMATE IN THE CENTRAL NERVOUS
and α-keto-β-methylvalerate, respectively: SYSTEM
L-Valine + α-Ketoglutarate ↔ L-Glutamate + Glutamate is the major neurotransmitter in the CNS and medi-
α-Ketoisovalerate ates the fast excitatory signaling needed for motor/sensory/
L-Leucine + α-Ketoglutarate ↔ L-Glutamate + α-Isocaproate autonomic processing, is an energy substrate, and is important
L-Isoleucine + α-Ketoglutarate ↔ L-Glutamate + α-Keto- for neurometabolic and neurovascular coupling. Astrocytes
β-methylvalerate. sense local glutamate activity and respond to this by eleva-
The 3 branched chain amino acids are sources of glutamate tions in the intracellular Ca2+ concentration. Also capable of
in the astrocyte.26,55-58 releasing glutamate, proposed mechanisms of release include
hemichannels, anion channels, and exocytosis.62-68 Functional
Decarboxylation to γ-aminobutyric acid integrity of astrocytes and neurons is necessary for transfer and
Decarboxylation of glutamate by glutamic acid decarboxyl- processing of information determined by glutamate release and
ase (GAD) results in the inhibitory neurotransmitter GABA concentrations. Involvement of glutamate in the pathogenesis
(Figure 1). Two isozymes, GAD65 and GAD67, are restricted of CNS diseases due to excessive release, reduced uptake,
to neurons and primarily GABAergic neurons and catalyze and/or alteration of receptor function has been postulated.69-80
the reaction: Critical to maintaining CNS integrity and preventing neuro-
L-Glutamate → GABA + CO2. pathology, glutamate homeostasis is an important function of
GABA is released by the neuron and taken up by astrocytes. astrocytes. Initially considered to be “glue” keeping the nerve
Metabolism of GABA in the astrocyte to the TCA cycle cell elements together and involved in various housekeeping
intermediate succinate is catalyzed by GABA-transaminase functions, astrocyte function in the tripartite synapse (synapse
and succinic semialdehyde dehydrogenase, the GABA shunt: between a pre- and post-synaptic neuron with bidirectional
GABA + α-Ketoglutarate ↔ Succinic Semialdehyde + L- communication with one astrocyte) emphasizes astrocyte
Glutamate participation in synaptic signaling. This is done through
Succinic Semialdehyde + NAD+ → Succinate + NADH. exchanging information with the pre- and postsynaptic neu-
Glutamate is a product of the first reaction. rons, responding to synaptic activity, and regulating synaptic
activity.81-85 Energy substrates and transmitter precursors are
Glutathione provided and waste products are removed. Close proximity
GSH is a major water soluble antioxidant of the brain, is to large numbers of neurons enables single astrocytes to pro-
26 Medical Gas Research ¦ March ¦ Volume 9 ¦ Issue 1
mote synchrony of neuronal action potential firing resulting tivation occurring within milliseconds to neuronal activity and
from glutamate release.86-89 Adaptive to their environment, neurotransmitters released at synapses. Fast responses occur
astrocytes are able to change the expression of large numbers as changes in intracellular free Ca2+ concentration occur.101-103
of proteins affecting CNS function. Heterogeneity in astrocyte Neurotransmitters released from neurons are thought to acti-
receptor expression, gap junction coupling, membrane currents vate receptors at the astroglial membrane inducing activation
and morphology occur between and within brain regions re- of phospholipase C and the concomitant production of IP3
sponding to and resulting in dynamic physiology.90-94 Interplay which triggers release of endoplasmatic reticulum Ca2+.104,105
between neuronal signaling to astrocytes and astrocytic signal- Hemichannels open and other Ca2+ dependent neurotransmit-
ing to neurons involve ATP and glutamate which coordinately ter release mechanisms are activated. Hemichannel opening
activate astrocytes through mobilization of their internal Ca2+. allows release of glutamate into the extracellular space which
This triggers release of neuroactive molecules including ATP can activate purinergic or NMDA receptor channels in as-
and glutamate from astrocytes. Ca2+ waves are generated in trocytes and induce changes in free Ca2+ concentration.106,107
astrocytes and neuronal synaptic transmission and neuronal Low glutamate concentrations result in short-acting Ca2+
excitability are modulated.95 oscillations in single astrocytes. Higher concentrations result
Presynaptic factors (release probability, quantal content, in astrocyte-to-astrocyte propagating Ca2+ waves.108 Different
vesicle composition), modulation of the concentration and neurotransmitters result in different Ca2+ responses in astro-
longevity of glutamate in the extracellular space (diffusion, cytes and may be able to activate entire astroglial networks.109
actions of glutamate transporters), and postsynaptic factors Because astrocytes envelope synapses, release of glutamate
(types and locations of ionotropic glutamate receptors, their also activates neighboring pre- and post-synaptic neurons
numbers, and nature and locations of associated intracellu- and, therefore, modulate surrounding synaptic activity.110,111
lar signaling systems) modulate excitation at glutamatergic
synapses. Molecular components include synthesis and Synthesis and release of glutamate
release of glutamate, glutamate-gated ion channel receptors Glutamate has to be present in the right concentration, in the
(iGluRs), glutamate G-protein-coupled receptors (GPCRs), right place, and for the right amount of time to regulate brain
and glutamate transporters. Membrane receptors for most development, cellular survival, differentiation, glutamate
major neurotransmitters and neuromodulators are expressed elimination, and formation and elimination of synapses.
by astrocytes and are important for neural communication, There are no special or unique synthetic or degradative en-
memory formation, learning, and regulation. Neurotransmitter zymes for L-glutamate – the amino acid is synthesized from
receptors form ion channels to mediate rapid membrane po- α-ketoglutarate and glutamine. Loss of glutamine may result,
tential changes, exert their action through slower intracellular but its replenishment is ensured by other biochemical path-
signaling pathways, and serve as synaptic scaffolds to regulate ways noted above.
synapse formation and maintenance (non-ionotropic function). Spontaneous release of glutamate from astrocytes helps
These receptors usually are not specific for glutamate and to set the basal probability of neurotransmitter release via
receptors (classified based on mammalian pharmacology and metabotropic glutamate receptor activation.112 K2P channels
identified as being ionotropic or metabotropic, responsible in astrocytes (isoforms TWIK1, TREK1, TREK2, TASK1,
for the glutamate-mediated postsynaptic excitation of neural and TASK3) are also critical for glutamate release.113-115
cells, and functions include modulation of synaptic plasticity) In astrocytes that are part of a tripartite synapse, calcium
result when sixteen functional subunits assemble in tetrameric oscillations cause proximal and distal release of glutamate
complexes to form GluR1–GluR4 for α-amino-3-hydroxy-5- to surrounding neurons.116 After release of glutamate from
methyl-4-isoxazoleproprionic acid (AMPA) receptors(occur in neurons, transport of glutamate to astrocytes, conversion of
2 alternatively spliced versions, flip and flop), GluR5–GluR7 glutamate to glutamine in astrocytes, transport of glutamine
and KA1–KA2 for kainate receptors, and GluN1, GluN2A- from astrocytes to neurons and reconversion of glutamine
GluN2D, and GluN3A–B for N-methyl-D-aspartate (NMDA) to glutamate in neurons completes the glutamate/glutamine
receptors.90 AMPA receptors, kainate receptors, and NMDA cycle. Astrocytic regulation ensures that greater than 60% of
receptors are ionotropic glutamate receptors in humans. synaptic glutamate is processed by the associated astrocyte.
Metabotropic glutamate receptors (mGluRs), GPCRs that bind Swelling and shrinking of astrocytes may allow reduction of
glutamate within a large extracellular domain and transmit leakage and/or prevent spillover of glutamate.
signals through the receptor protein to intracellular signal-
ing receptors, are classified into three groups based on their Glutamate-gated ion channels
sequence homology, pharmacological profile, and coupling iGluRs, integral membrane proteins, are important to CNS
to intracellular transduction pathways – Group I mGLuRs synaptogenesis, neuronal pathfinding, neuronal viability,
consist of mGlu1, mGlu5, and their splice variants; Group II and regulation of synaptic efficacy.117 These are ligand-gated
includes mGlu2 and mGlu3; and Group III mGlu4, mGlu6, nonselective cation channels that result in flow of K+, Na+, and
mGlu7, mGlu8, and some splice variants.91,92 While functional Ca2+ with glutamate binding. Excitatory postsynaptic current
heterogeneity of these components between astrocytes within results and is depolarizing. Excitatory synaptic transmission in
and across brain regions exists, impact on physiological and the human brain depends on a high concentration of glutamate
clinical presentations remains undefined.93,94,96-100 at the postsynaptic membrane after its release from presyn-
The intracellular signaling cascades depend on astroglial ac- aptic terminals. iGluRs are the major mediators of excitation

and activation of AMPA receptors, NMDA receptors, and/or synaptic transmission, and neuroplasticity.129 Altering the
kainate receptors and require proximity of the amino acid. Ion number of AMPA receptors is the basis of synaptic neuroplas-
channel pores formed by these receptors activate with binding ticy – synapses become stronger with the addition of AMPA
of glutamate. Overstimulation results in neurodegeneration receptors.130,131 Subunit composition varies depending on the
and neuronal damage due to excitotoxicity. Synaptic plasticity brain region and the functional properties of AMPA receptors
and molecular mechanisms of learning and memory are also and their trafficking depend on subunit composition.132,133 The
dependent on iGluRs. majority of AMPA receptors in the CNS contain GluA2 which
Major neurological and neurodevelopmental disease pro- is important for changing Ca2+ permeability and resulting
cesses are associated with iGluR mutations, misexpression, synaptic transmission and intracellular signaling.134 AMPA
misregulation, or deficits in signaling.118-125 Encoded by 18 receptor Ca2+ permeability depends on the GluA2 subunit
genes which coassemble to form 3 major families (AMPA, mRNA and mediates fast excitatory synaptic transmission in
NMDA, and kainate), these receptors form tetrameric ligand- the CNS. Incorporation of the GluA2 subunit reduces the Ca2+
gated channel pores that allow influx of Na+ and Ca2+. AMPA permeability and channel conductance and prolongs the decay
iGluR subunits include GluA1, GluA2, GluA3, and GluA4, kinetics of a synaptic current.135 A switch in AMPA receptor
NMDA subunits GluN1, Glun2A, GluN2B, GluN2C, GluN2D, phenotype during physiological functioning and under patho-
GluN3A, and GluN3B, and kainate subunits GluK1, GluK2, logical conditions results in a change in information processing
GluK3, GluK4, and GluK5. A fourth family is formed by the and Ca2+-dependent signaling at synapses.136
delta subunits GluD1 (GluRδ1) and GluD2 (GluRδ2). In the
brain, GluA1/GluA2 (AMPA receptor subtype), GluN1/Glu- N-methyl-D-aspartate receptors
N2A/GluN2B (NMDA receptor subtype) and GluK2/GluK5 Astrocyte AMPA receptors and NMDA receptors differ in their
(kainate receptor subtype) are the most widely expressed. sensitivity to glutamate as well as their desensitization rate and
Composed of 4 large subunits, iGluRs contain 4 discrete provide information about the concentration and duration of
semiautonomous domains – the extracellular amino-terminal glutamate in the synaptic cleft. The latter form glutamate-gated
domain, the extracellular ligand-binding domain, the TMD ion channels that are highly permeable to Ca2+ (main source
– harbors the ion channel, and an intracellular C-terminal do- of calcium responsible for glutamate-induced excitotoxicity),
main. Binding of glutamate to the extracellur ligand-binding relay physiological signals into neurons, and trigger intracel-
domain allows the influx of ions and generation of synaptic lular signaling cascades that can lead to cell death.16 NMDA
current in the brain. Various ionotropic glutamate receptors receptor activation resulting in increased Ca2+ concentrations
on postsynaptic cells determine potentiation or depression triggers synaptic plasticity and amount and kinetics of the
of the cell. Glutamate, acting on glutamate receptors, causes calcium influx determine physiology.137 Essential but po-
Ca2+ to influx into the postsynaptic cell resulting in a cascade tentially harmful, subunit composition of NMDA receptors
of cell processes that can result in damage to cell structures, determines functionally distinct CNS properties.138,139 Seven
and, possibly, cell death. Clinical neuropathology associated subunits have been identified – GluN1 (8 isoforms), GluN2A,
with glutamate excitotoxicity include traumatic brain injury, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3b – and are
cerebral ischemia, hyperalgesia, attention deficit hyperactiv- brain region-specific. All of the subunits have 4 domains, the
ity disorder, autism, Huntington’s disease, multiple sclerosis, N-terminal domain, the agonist binding domain, the TMD,
Parkinson’s disease, Rasmussen’s encephalitis, schizophrenia, and the intracellular C-terminal domain. N-terminal domain,
seizures and, possibly, acquired immune deficiency syn- agonist binding domain, and TMD are targeted by endogenous
drome dementia complex, Alzheimer’s disease, amyotrophic or synthetic allosteric modulators.140
lateral sclerosis, combined systems disease (vitamin B12 Ongoing modification of subunit composition with re-
deficiency), depression, anxiety, drug addiction/tolerance/ sultant changes in biochemical interactions and physiology
dependency, glaucoma, hepatic encephalopathy, hydroxybu- continues throughout life. Composition of their heterotetra-
tyric aminoaciduria, hyperhomocysteinemia, homocysteinuria, meric assembly, usually two GluN1 and two GluN2 subunits,
hyperprolinemia, lead encephalopathy, Leber’s disease, mi- determines function of the NMDA receptors. GluN1 and
tochondrial encephalopathy, lactic-acidosis, and stroke-like GluN2-containing NMDA receptor complexes are abundant
episodes syndrome, myoclonic epilepsy with ragged-rebfibers, throughout the CNS. GluN2 subunits define channel proper-
mitochondrial abnormalities, neuropathic pain syndromes, ties and subcellular localization of the receptor. Diheteromeric
nonketototic hyperglycinemia, olivopotocerebellar atrophy, (GluN1/GluN3) or triheteromeric (GluN1/GluN2/GluN3)
essential tremor, Rett syndrome, sulfite oxidase deficiency, complexes are formed if GluN3 subunits are incorporated.140
Wernicke’s encephalopathy, and depersonalization disorder. Combinations of subunit assembly results in functionally
different NMDA receptors and physiologic differences in the
α-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid CNS. Although GluN1 is ubiquitously expressed in the CNS,
receptors developmental and regional variations depend on the type
Widely expressed in the adult brain, AMPA receptors are the of GluN1 isoform.140 GluN2A–D, forming glutamate-gated
first iGLuRs to appear during CNS development.126-128 Most ion channels that are heterogeneous and widely permeable
excitatory synaptic transmission in the CNS is mediated by to calcium ions, result in normal neurophysiology as well
glutamate through activation of AMPA receptors. Interac- as neuropathology depending on the receptors functional
tion of postsynaptic proteins with AMPA receptor subunits properties. GluN2B-NMDA receptors have a higher affinity
control AMPA receptor insertion, location, pharmacology, for glutamate.140 Extrasynaptic NMDA receptors have higher
levels of GluN2B-containing heterodimers, are distinct, and sequence homology. Recent animal studies show that these
probably serve a specific function.16 The GluN3-containing receptors are upregulated during postnatal development and
NMDA receptors are not as common as those composed only play a role at excitatory synapses in neuronal networks in the
of GluN1 and GluN2 subunits.139 In the CNS, they are impor- adult brain.157 GluD1 is predominately expressed in the inner
tant in delaying synapse maturation until the arrival of sensory ear and is important for high-frequency hearing and GluD2 is
experience and in targeting non-used synapses for pruning. predominatenly expressed in cerebellar Purkinje cells and is
Reactivation of GluN3A expression at the wrong time may important for motor coordination and motor learning. GluD2
result in neuropathology.141 contribute to synaptic formation through interaction with
cerebellin precursor protein 1 and presynaptic Neurexin. The
Kainate receptors latter binds to the N-terminal domain of GluD2 and regulates
Another member of the ionotropic glutamate receptors, kain- formation and maintenance of parallel fiber-Purkinje cell
ate receptors, form from 5 subunits (GluK1, GluK2, GluK3, synapses. Both receptors are widely expressed in other brain
GluK4, and GluK5) into tetrameric ion channels. GluK1–3 can regions.158-161
form homomeric and heteromeric receptors whereas GluK4–5 These delta receptors possess functional ion channel pores,
must form heteromeric receptors with one of the GluK1–3 but ligand binding at the ligand-binding domain may only
subunits to form functional channels.142-146 The former are result in desensitization-like conformation channels. Receptor
low-affinity kainate receptors and the latter high-affinity domains, except the ligand-binding domains, of GluD1 and
kainate receptors.147 GluK5 is widely distributed through the GluD2 are capable of ligand-gated ion channel function.162
CNS and in heteromeric complexes with GluK2 constitutes GluD1 regulates the connectivity of parallel fiber-interneurons
the most abundant kainate receptor subtype in the brain.146,147 synapses and this results in differentiation and/or survival of
Located at pre- and postsynaptic membranes of neurons molecular layer interneurons. This is done with the help of
and astrocytes in the CNS, kainate receptors are constituents GluD2 and results in cerebellar synaptic wiring.163,164 Glutamate
of excitatory synaptic transmission and modulation of excit- binding to mGlu1 has also been shown to result in GluD2 ion
ability by regulating neurotransmitter release. In an experi- channel activity and contributes to slow excitatory postsynaptic
mental mode of temporal lobe epilepsy, Vargas et al showed currents in Purkinje cells.165 An allosteric interaction between
an increase in astrocyte expressed kainate receptor subunits amino-terminal domain and ligand-binding domain layers for
(GluK1, GluK2, GluK3, GluK4, and GluK5) following status GluD2 is thought to be due to anchoring of GluD2 to the Nrx-
epilepticus. The authors suggested that this may serve as a sen- Cbln1 complex which limits motion of the amino-terminal
sor for excess glutamate.148 Astrocyte response to extracellular domain layer and allows D-serine-induced conformational
glutamate is propagation of intracellular Na+ waves resulting changes to be transmitted to the TMD and C-terminal domain.
in activation of glial Na+/K+-ATPase which increases energy
demand inside the astrocyte.149 Increased energy demand and Glutamate G-protein-coupled receptors
glucose consumption inside the astrocyte provides metabolic As the most abundant receptor gene family in the human
substrates to neurons through the astrocyte-to-neuron lactate genome, GPCRs are membrane bound proteins activated by
shuttle and provide energy substrates for injured surviving extracellular ligands through interactions with G proteins
neurons.150 Functioning kainate receptors may also trigger – a family of proteins that act as molecular switches inside
release of gliotransmitters – glutamate release from astrocytes cells and are regulated by factors that control their ability to
has been implicated in hippocampal slice models of seizure bind to and hydrolyze guanosine triphosphate to guanosine
activity.158,159 Increased Ca2+ signaling, hypothesized to result diphosphate. Conformational changes of the GPCR result in
from pathological expression of kainate receptors in reactive activation of the G protein which is composed of a heterotri-
astrocytes, may cause synchronization of neurons due to glu- meric complex of α, β, and γ subunits. Activation of G protein
tamate and result in hyperexcitability. Both may contribute to subunits then modulates the function of effector molecules.
the pathophysiology of epilepsy151,152 and differences in NMDA The GPCR family has several subgroupings, the majority
receptors and kainate receptors in astrocytes are associated of classical neurotransmitter GPCRs belonging to family
with delayed neuronal death in the injured brain – functional A. mGluRs belong to Class C GPCRs which also includes
astrocyte loss is considered a cause of neuronal death in the GABAB receptors, calcium-sensing receptors, pheromone
injured CNS as vulnerability of astrocytes to NMDA and kainic receptors, and taste receptors.166,167
acid are associated with delayed neuronal death.153 Partially Eight mGluR subtypes have been identified and are sub-
Ca2+-permeable, kainate receptor activation also results in an classified into three groups based on sequence homology,
influx of Ca2+ ions and the resulting Ca2+ waves within the G-protein coupling, and ligand selectivity. mGluRs 1 and 5
astrocytic syncytium may lead to the release of gliotransmit- are in Group I, mGluRs 2 and 3 in Group II, and mGluRs 4,
ters from astrocytes.154,155 In hippocampal neurons, released 6, 7, and 8 in Group III. Groups I and II are present in neurons
glutamate triggers a slow, transient, current which can activate with mGluR3 and mGluR5 also being present in astrocytes.
NMDA receptors156 and/or activates GluK5-containing kainate Group III mGluR are not present in astrocytes, are predomi-
receptors on interneurons and increases inhibitory postsynaptic nantly presynaptic, and mGluR6 expresses its effects in retina.
currents.147 Signaling pathways of Group I mGluR include phospholipase
C stimulation, stimulation of adenylyl cyclase, and MAP
Delta receptors kinase phosphorylation, that of Group II include inhibition
GluD1 and GluD2 form this iGluR sub-family because of of adenylyl cyclase, activation of K+ channels, and inhibition
of Ca2+ channels, and that of Group III include inhibition of malities result in distinct clinical patterns.177 GLAST-deficient
adenylyl cyclase, activation of K+ channels, and inhibition of mice display longer seizure duration. Human mutations are
Ca2+ channels (The mGluR6 in the retina initiates a signal trans- associated with ataxia and seizures.178-180 While neuron-specific
duction cascade used by depolarizing bipolar cells to convey glutamate transporters are not important for survival, behav-
the light-induced decline in photoreceptor glutamate release ioral abnormalities have been observed.181,182 Although diffu-
to retinal ganglion cells). mGluRs contain a large extracellular sion is the major mechanism governing synaptic glutamate
N-terminal domain, the Venus flytrap domain (VFD), has two concentration, glutamate transporters are also key regulators
lobes and bind glutamate in a cleft between them. This dimer of synaptic transmission and termination of transmission.
may be open-open (inactive), open-closed, or closed-closed. Glutamate existence in the synaptic cleft is short, about 1.2 ms,
The latter two are induced by binding of ligand. VFD’s can and concentration is high, 1 mM. While AMPA- and NMDA-
also bind divalent cations which can potentiate or activate the glutamate receptors become desensitized with prolonged ex-
receptor. The signal induced by ligand binding is transmitted posure to the neurotransmitter, glutamate transporters actively
from the VFD’s through cysteine-rich domains. A disulfide control duration of excitatory transmission by competing for
bridge linking the VFD and cysterine-rich domain may be glutamate in the synapse and is related to astrocytic coverage of
required for propagation of signals induced by agonist bind- synapses – controls presynaptic glutamate receptor activation
ing to mGluRs. The heptahelical domain of the mGluRs may through glutamate uptake. Critical during high activity and/
regulate G protein coupling specificity. Modulators of mGluRs or multisynapse transmission, glutamate transporters control
affecting glutamate activity bind within the hepatohelical glutamate receptor activation and spillover of glutamate
domain and may positively or negatively influence glutamate between synapses and, thus, maintain specificity of synaptic
activity. Modulation of G protein coupling also occurs at the transmissions.
C-termini of mGluRs.167
Activation of mGluR by glutamate may require binding of WHAT HAPPENS WITH TOO MUCH GLUTAMATE IN THE
both protomers, may depend on the mGluR group, and result in CENTRAL NERVOUS SYSTEM?
Ca2+ mobilization and activation of protein kinase C. Ion chan- Glutamate excitatory signaling is needed for most motor,
nels on the plasma membrane are indirectly activated through sensory, and autonomic processing, memory formation,
a signaling cascade involving G proteins. Binding of glutamate and normal brain development – physiologic activity being
to mGluR1 results in an increase in Ca2+ in the cytoplasm, determined by the balance of synaptic excitation and inhibi-
that of mGluR5 release of K+ from the cell by activating K+ tion (the E/I balance). Glutamate, the predominant excitatory
channels, that of mGluR2 and mGluR3 result in inhibition of neurotransmitter in the CNS, is normally restrained by inhibi-
adenylyl cyclase causing shutdown of the cAMP-dependent tory mechanisms, but an increase in the number of glutamate
pathway and thereby decreasing the amount of cAMP, and that synapses, enhanced glutamate synaptic function, and/or
of mGluR4, mGluR6, mGluR7, and mGluR8 result in activa- increased extracellular glutamate concentrations result in an
tion of Ca2+ channels allowing more Ca2+ to enter cells.168-172 imbalance and the excess glutamate effect may result in mas-
sive neuronal death and brain damage due to excitotoxicity.
Glutamate transporters Control of glutamate clearance which results in low extracel-
Excitatory signaling, neurovascular coupling, glutamate/meta- lular glutamate and less excitotoxicy is an important function
bolic pathways, glycolytic enzymes/glycolysis, mitochondria/ of astrocytes.183 Astrocytes have receptors regulated by the
oxidative phosphorylation, glycogen phyosphorylase/glycogen neurochemical environment that allow them to determine
synthetase, Na+/Ca2+ exchangers, and Na+/K+-ATPase depend neuronal transmission. Activation of these receptors results
on glutamate transporters that are present on astrocytes and in changes of ion concentrations (mainly Ca2+ and Na+) in the
neurons. Critical for normal brain function, the family of cytoplasm of the astroglia which regulate astroglial functions
brain glutamate transporters includes excitatory amino acid and act as a substrate for astroglial excitation.184-188 Complex
transporters 1 to 5 (EAAT1–5). All transport L-glutamate and, interactions between the blood vasculature, interposing cere-
during one transport cycle, the transporter binds one extracel- brospinal fluid, and surrounding interstitial fluid are facilitated
lular molecule of glutamate, three sodium ions, and one pro- by astrocytes as well and influence neurotransmitter concentra-
ton. Conformational changes result in these substrates being tions.188 Glutamate homeostasis determined by astrocytes in
released into the cytoplasm. To complete the cycle, a potassium these dynamic processes is not well defined.
ion in the cytoplasm is bound to the transporter and confor- Although synaptogenesis and synaptic maturation proceed
mational changes result in the potassium being released into through formation of an initial contact between the terminal
the extracellular space. EAAT’s can also function as chloride and postsynaptic neuron, maturation of the synapse, stabi-
channels and may be considered inhibitory glutamate recep- lization and maintenance, and elimination, survival time
tors.173-175 EAAT1 (GLAST) and EAAT2 (GLT-1) are mainly and contribution of synapses varies. Control of extracellular
located on astrocytes. EAAT3–5 are exclusively neuronal. glutamate and neuronal glutamate pools by astroglia regulate
Synaptic transmission is dependent on extracellular gluta- extracellular glutamate concentration by balancing uptake
mate concentration. Impaired GLT-1 results in an increase in through Na+-dependent astroglia-specific glutamate trans-
extracellular glutamate levels and, in GLT-1 knockouts, result porters (SLC1A3/EAAT1 and SLC1A2/EAAT2) and release
in hyperactivity and severe seizures.176,177 In animal models, mainly through the cysteine-glutamate exchanges of systemic
astrocytic GLT-1 and neuronal GLT-1 are different and abnor- Xc- (SLC7A11). The astroglial cradle regulates these processes

and isolates synapses within the territory of a single astrocyte lipid peroxidation of microsomal lipids and phospholipids, and
and prevents neurotransmitter spill-in and spill-over. While reduction of cytochrome b5. Endogenous CNS CO is critical
point-to-point transmission of glutamate across a synapse for the normal functioning, neuroprotection, and neurorepair of
has been the conventional view of glutamate neurophysiol- the brain. Synthesis, transactions, and disposition are clinically
ogy, glutamate spillover due to escape of glutamate from the relevant for neurodevelopment, neuropathology, and neuro-
synaptic cleft results in glutamate accumulating in the extra- therapy. A neurotransmitter, endogenous CO is dependent on
synaptic space as well. Glutamate concentrations vary greatly brain heme oxygenase isozymes, heme oxygenase-1 (HO-1)
between plasma, cerebrospinal fluid, intracellular fluid, and (primarily localized in the endoplasmic reticulum) and heme
extrasynaptic fluid. Computational models suggest that extra- oxygenase-2 (HO-2) (primarily anchored to the endoplasmic
cellular glutamate concentrations are regulated differently in reticulum). These catalyze the first and rate-limiting step in
the synaptic, perisynaptic, and nonsynaptic subcompartments the degradation of heme to iron, biliverdin, and CO. CNS cy-
and regulates or results in pathology of synaptic transmission, toprotective effects are attributed to CO194 and are mimicked
synaptic plasticity, synaptic crosstalk, nonsynaptic neuro- by low dose exogenous CO (inhaled CO and CORM’s). In-
transmission, neuronal survival, gliotransmitter release, and/ creased CO production by upregulation of heme oxygenases
or hemodynamic responses.189-193 has been targeted for neuroprotective and neurotherapeutic
E/I imbalance contributes to acute and chronic CNS neu- effects and exogenous administration of CO or CORM’s and/
rodevelopmental and neurologic disorders. If extracellular or targeting of heme oxygenases to increase the production
glutamate rises to above normal, glutamate receptors are of CO have been suggested as treatment for multiple CNS
overactivated and intracellular reactions in the postsynaptic disease processes.195-205
neurons result in cell injury and possibly death due to exci- CNS CO signal transduction pathways result in vasoactive,
totoxicity. Astroglial glutamate transporters coordinate this antithrombotic, anti-proliferative, neurotransmission, anti-
excitatory signaling and brain energetics. These transporters inflammatory, and/or anti-apoptotic effects.206 CO interaction
co-localize with, form physical interactions with, and couple with soluble guanylate cyclase (sGC) via the sGC/cGMP path-
to energy-generating systems (Na+/K+-ATPase, Na+/Ca2+ ex- way is associated with vascular effects (platelet aggregation,
changer, glycogen metabolizing enzymes, glycolytic enzymes, dilation, profibrinolysis, and anti-inflammation) and down-
and mitochondria/mitochondrial proteins). Glutamate uptake regulation of cell proliferation. In the latter, CO upregulates the
p38 mitogen activated protein kinase (p38β MAPK) and p21
regulates these processes and the process may regulate glu-
resulting in downregulation of cell proliferation. CO effects
tamate uptake.191 Transporters remove the extra extracellular
on p38β MAPK affect apoptosis (through antiapoptotic genes
glutamate via a sodium-potassium couple uptake mechanism.
and caspase activation) and inflammation (through heat shock
If not removed, excess glutamate has been associated with
factor-1, interleukin-10, interleukin-1β, interleukin-6, tumor
neural damage and results in high levels of Ca2+ to influx
necrosis factor-α, and macrophate inflammatory protein1β).206
into the postsynaptic cells. Cell degradation due to proteases,
Induction of the heme oxygenases has resulted in elevated
lipases, nitric oxide synthetase, and enzymes that affect cell
CO levels and are thought to be neuroprotective as well as
structures results. A cycle of positive feedback cell death can
neurotherapeutic.
lead to neurodegeneration. Oxidative stress is also affected.
As astrocytes are critical for the homeostasis of glutamate
High synaptic glutamate levels reverse cysteine/glutamate and resultant excitotoxicity and neuropathology, further evalu-
antiporter (transports cysteine into the cell and glutamate out). ation of CO effects on astrocytes and the biophysiological
Glutathione, an antioxidant, is not synthesized at the appropri- interactions affecting glutamate homeostasis is needed. CNS
ate levels. This leads to more ROS that injure the cells which astrocytes are now targeted for treating neurological disorders
then cannot process glutamate. Nitric oxide synthase is also as non-neuronal cells (which include astrocytes) outnumber
activated by the high concentration of glutamate with a result- neurons, vesicle-based release of transmitter is present in
ing over production of nitric oxide – damages mitochondria. astrocytes although the kinetics is slower than in neurons,
Astrocyte homeostasis of glutamate is important in regulating and astrocytes contain glycogen which is converted into L-
these complex interactions.181-185 lactate, a fuel and signalling molecule important to cognition
and neuroprotection and an alternative energy source during
POSSIBLE BIOCHEMICAL EFFECTS OF CARBON excitotoxic brain injury. CO is thought to increase L-lactate.207
MONOXIDE ON ASTROCYTE GLUTAMATE HOMEOSTASIS Exposure of cortical neurons to glutamate increases HO-2
CO is a gasotransmitter: 1) It is a small molecule of gas; 2) It activity and CO production. Upregulation of CNS HO-1 also
is freely permeable to membranes; 3) It can have endocrine, results in an increase of CO. Astrocyte heme oxygenases can
paracrine, and autocrine effects; 4) It is endogenously and en- also be upregulated thereby increasing the production of CO.
zymatically generated and its production is regulated; 5) It has Diffusion of the gas to different cell types and cell organelles
well defined and specific functions at physiologically relevant result in effects on biochemical pathways. The effects of
concentrations; and 6) Its cellular effects may or may not be CO on astrocyte homeostasis of glutamate and prevention
mediated by second messengers, but have specific cellular of excitotoxicity with resultant neuropathology, most likely,
and molecular targets. CO is cytoprotective and at least 86% involve multiple pathways as well as intra and extracellular
originates from heme metabolism. Heme-independent sources structures that result in communication between cells and
include auto- and enzymatic-oxidation of phenols, photo- within cells.206,208-216 Important for CNS homeostasis, astrocyte
oxidation of organic compounds, iron-ascorbate catalyzed glutamate metabolic pathways, uptake of glutamate by astro-
cytes, and release of glutamate from astrocytes are affected tions. Glutamate, considered to be partly responsible for the
by the presence or absence of CO. mobility of astrocyte mitochondria, is cleared into astrocytes
via GLAST and GLT1 (EAAT1 and EAAT2). These catalyze
Glutamate metabolic pathways glutamate and aspartate transport against a concentration gradi-
Cellular energy ent with three Na+ ions and a H+ with the counter-transport of
Mitochondrial energy production is modulated based on cel- a K+ ion. Na+/K+ ATPase is activated which results in reversal
lular needs and bioenergetic constraints. ATP is responsible of the Na+/Ca2+ exchanger leading to increases in Ca2+.233-235
for most of the energy in cells. Mitochondrial respiration Mitochondria movement is regulated by glutamate uptake and
determines, to a large extent, this cellular energy, depends on is directly related to the concentration of Ca2+. Inhibition of
oxidative phosphorylation (consists of the electron transport glutamate uptake increases mobile mitochondria in astrocyte
chain (ETC) and ATP synthase), and plays an important role processes. The movement of astrocyte mitochondria depends
in energy production and apoptosis.217-219 on cellular transport machinery, adaptor proteins that link
Regulation of the mitochondrial ETC and ATP synthase mitochondria to motor proteins. Mitochondrial Rho proteins
(result in the majority of cellular energy through cell signal- and trafficking kinesin binding proteins are thought to be im-
ing) limit reactive oxygen species (ROS) responsible for portant in the positioning of mitochondria to active processes
cell damage and the triggering of death processes, oxidative in astrocytes.236-238 Mitochondrial Rho proteins respond to
phosphorylation activity, mitochondrial membrane potential Ca2+ signaling – Ca2+ results in the arrest of mitochondria
hyperpolarization, release of CytC, formation of the apopto- within astrocyte processes in response to neuronal activity
some, and execution of apoptosis via caspase activation. Bio- and glutamate.226,227,237 Under normal conditions, mitochondria
energetic defects, respiratory chain-induced oxidative stress, approach endoplasmic reticulum allowing Ca2+ flow between
defects of mitochondrial dynamics, increased sensitivity to organelles – close apposition is needed. Formation of tethers
apoptosis, and the accumulation of damaged mitochondria that link the mitochondria with endoplasmic reticulum may
with unstable mitochondrial DNA have been associated be dependent on Miro proteins238-240 and affect other cellular
with energy defects. Mitochondria regulate Ca2+ signals and processes.
ionic homeostasis, synaptic development, blood flow, glucose CO targets mitochondria, including astrocyte mitochondria,
metabolism, glutamate clearance, plasticity, proliferation, at several levels: 1) Mitochondrial ROS, signaling molecules
coordinate local metabolism, provide energy, are dynamic, for CO-induced pathways, are increased with physiological
and integrate survival and death biochemical changes. There amounts of CO; 2) CO limits mitochondrial membrane per-
is extensive fission and fusion of these organelles, directed meabilization and thereby inhibits the release of pro-apoptotic
movement within cells, and controlled degradation. The for- factors into the cytoplasm; 3) CO increases the ability of the
mer is critical for development of the CNS and determine the mitochondria to take up Ca2+; 4) CO modulates mitochondrial
shape, connectivity, distribution, and density of mitochondria metabolism by increasing TCA cycle rate, oxidative phos-
within neurons and, probably, astrocyte processes. In astro- phorylation and mitochondrial biogenesis which increases
cytes, mitochondria are seen within the finer processes of the ATP; and 5) CO prevents excitotoxicity-induced cell death
cell, movement is regulated, and they contribute to local Ca2+ and modulates cell proliferation by limiting the activity of
signaling within the astrocyte. Protoplasmic astrocytes have T-type and L-type Ca2+ channels.241-246 CO, therefore, affects
highly branched processes and veil-like structures resulting ROS signaling and anti-oxidation, Ca2+-induced mitochon-
in a very large surface area to volume ratio and intimate as- drial membrane permeabilization, programmed cell death,
sociation with synapses (may exceed 2 million synapses in Ca2+ buffering, and metabolism. CO targets cyclooxygenase
the human brain).220 Astrocyte mitochondria are mobile (ar- (COX), the final electron acceptor of the mitochondrial elec-
rested by glutamate and Ca2+), change speed and direction, tron transport chain – catalyses oxidation of ferrocytochome
and movement depends on adaptor proteins and motor pro- c by gaseous oxygen. At high levels, CO results in high levels
teins.221-227 Mitochondrial movement in the astrocyte promotes of carboxyhemoglobin which exceeds the limit of toxicity.
distribution of mitochondria into cellular processes, allows However, at lower levels, COX-specific activity is dependent
retrograde movement out of the cell processes and into the on oxygen concentration and may activate hypoxia-inducing
cell body where degradation of mitochondria takes place, factor-1 which is involved in the regulation of COX subunits
improves fusion and fission processes which allow exchange for optimization of mitochondrial respiration. Hypoxia and
of proteins and genetic materials, promotes the regulation of CO presence have a synergistic effect on COX inhibition when
transfer of mitochondria between adjacent cells (horizontal the ETC is in a more reduced state. Low concentrations affect
transfer), and redistribution of mitochondria to sites needing the coupling between ATP production and respiration. Cyto-
increased energy production is facilitated.228-232 protection is associated with mitochondrial mild uncoupling
Astrocyte mitochondrial presence and activity are related to stimulation thus decreasing mitochondrial ROS production and
neuronal activity and, especially, glutamatergic activity. Inhi- is dependent on its concentration – at lower concentrations,
bition of neuronal activity increases activity of mitochondria increased respiratory control ratio and mitochondrial trans-
in astrocytes. Mitochondria are not uniformly distributed in membrane potential are seen whereas, at higher concentrations
astrocytes and their location at synapses and active regions is of CO, a decrease in respiratory control ratio and mitochon-
associated with neuronal activity – about 15% of the astrocytic drial membrane potential is seen. Brief exposure of astrocytes
mitochondria are mobile. The addition of glutamate decreases isolated from cortex increased cellular oxygen consumption
the percentage of mobile astrocyte mitochondria in prepara- with an improvement of mitochondrial respiratory chain and
oxidative metabolism. CO also stimulates mitochondrial bio- and is important for the control of mitochondrial respiration
genesis, important for cell metabolism and cell protection, and and calcium signaling and antioxidant defenses. Ca2+ on the
regulates mitochondrial respiratory complexes.247-252 external side of the inner mitochondrial membrane stimulates
Changes in astrocyte intracellular calcium occur with transport activity and the Ca2+-binding sites are localized and
exposure to CO and/or glutamate. Two different pathways are independent of Ca2+ entry into the mitochondria by calcium
have been identified. With glutamate, the metabotropic uniporter and activates the AGCs from the external face of the
response results in an initial Ca2+ spike that can propagate mitochondria.259,260 Glutamate delivered into the mitochondria
rapidly from cell to cell and probably involves IP3. This can through AGC’s is transaminated with intramitochondrial oxa-
produce oscillatory intracellular waves that propagate within loacetate to form aspartate and is not available for GDH. GC1
cells and are sustained only if external Ca2+ is present. The and GC2, unlike the AGC’s, function in forward or reverse
second response, the ionotropic response, results in sustained mode and provide substrate for GDH. GC1 and GC2 are
elevation in Ca2+and is associated with receptor-mediated Na+ equally expressed in the brain. GC’s are important in ureogen-
and Ca2+ influx, depolarization, and voltage-dependent Ca2+ esis, glutamate derived from GC’s produce NH3. Direction of
influx. CO, involved in Ca2+ signaling and in the modulation transport of glutamate is dependent on the energy state of the
of Ca2+ channels, inhibits L-type Ca2+ channels and may be mitochondria and is controlled by mitochondrial metabolism.
cytoprotective. This has not been demonstrated in astrocytes. Aspartate, important to the homeostasis of astrocyte gluta-
CO has also been implicated in preventing activity of T-type mate biochemical pathways, can only exit the mitochondria
Ca2+ channels, and regulation of intracellular organelle Ca2+ in exchange for glutamate. The former is expressed in the
stores. The direct effect of CO on Ca2+ signaling in the astrocyte mitochondrial matrix of astrocytes. Normally, astrocytes me-
mitochondria is not known, but glutamate-induced calcium sig- tabolize glutamate via cytosolic GS resulting in glutamine.259
nals stimulate CO production in astrocytes.235,246,253-256 Further When extracellular glutamate exceeds 0.5 mM, the amount
studies are needed to evaluate the role of CO in mitochondria metabolized via the TCA cycle in the mitochondria increases
and glutamate homeostasis. significantly and, if energy is needed, glutamate is metabo-
lized primarily by GDH – glutamate enters the TCA cycle
Mitochondrial glutamate versus cytosol glutamate and as α-ketoglutarate after deamination catalyzed by GDH and,
carbon monoxide ultimately, catabolism of glutamate to CO2 with the production
Transport of keto acids, amino acids, nucleotides, inorganic of ATP. Transport of glutamate from the cytosol across the
ions, and co-factors across the mitochondrial inner membrane mitochondrial membrane is by the AGC and the GC - AGC
is dependent on the mitochondrial carrier family - mitochon- requires aspartate in exchange of glutamate and GC glutamate
drial glutamate pathways being controlled by mitochondrial is transported with a proton. AGC requires a concentration
enzymes and transmembrane carriers (especially GDH and gradient of solutes and/or electrochemical potential across the
mitochondrial glutamate carriers, respectively). Biochemical inner mitochondrial membrane and is a Ca2+ sensor259 which
pathways between the cytosol and the mitochondrial matrix may be involved in Ca2+ signaling. In addition to their role in
result and are essential for synthesis of ATP from oxidation of glutamate and aspartate exchange, AGC 1 (Aralar1) and AGC
sugars and fats, synthesis of heme and iron sulphur clusters, 2 (citrin carriers) are part of the malate-aspartate shuttle that
production of heat, macromolecular synthesis, and the synthe- is needed for transfer of reducing equivalents from cytosolic
sis, degradation, and interconversion of amino acids. Regula- NADH into mitochondria (and activates ETC) leading to ATP
tion of GDH activity has been suggested as a neurotherapeutic generation.
approach – neuronal mitochondrial activity is improved and Calcium signaling is necessary to the function of GDH and
excitotoxic risk reduced with increased GDH activity.256 Simi- the mitochondrial glutamate carriers. Matrix Ca2+ is known to
lar studies on astrocytes have not been done. The mitochondrial be important to mitochondrial function and the regulation of
glutamate carriers, also important to glutamate homeostasis, glutamate transport by extramitochondrial Ca2+ may further
consist of six trans-membrane α-helices and three matrix determine their roles. AGC’s are activated by low extramito-
helices arranged with threefold pseudo-symmetry – substrate chondrial levels of Ca2+. CO affects Ca2+ concentrations and,
binding site is accessible from the intermembrane space of therefore, probably GDH and mitochondrial glutamate carriers.
the mitochondrion. Required for normal CNS function, two Further studies are needed.
aspartate-glutamate carriers (AGC: aralar and citrin) – opening
and closing of the carrier and substrate binding may depend Precursors and intermediates
on disruption and formation of two salt bridge networks – and In the CNS, neurovascular coupling regulates energy sup-
two glutamate/hydroxyl carriers (GC1 and GC2) are present ply required for fluctuating energy needs. Astrocyte-neuron
in astrocytes. metabolic cooperation result in spatial and temporal delivery,
The aforementioned AGC’s are classified as strict exchang- production, utilization, and storage of energy for the brain –
ers or uniporters and are electrogenic.257 Precursor proteins astrocytes, glutamate, and CO are essential to this process.
are synthetized in the cytosol and then are transported to Astrocytic processes cover approximately 63% of capillaries,
mitochondria membranes. Astrocytes express both aralar and allow detection of neuronal activity (and, therefore, energy
citrin – AGC1 (aralar) is important to glutamate-mediated requirements), and affect local vascular supply which increases
excitotoxicity in the mature CNS and muscles. Both supply or decreases availability of energy substrates. Afferent activity
aspartate that is produced in the mitochondrial matrix to the results in release of excitatory neurotransmitters from presyn-
cytosol in exchange for cytosolic glutamate plus a proton258 aptic sites and results in an increase of astrocyte glutamate.
Glutamate stimulates CO production by astrocytes which is α2 isoform is mainly expressed in astrocytes. CO regulates
needed for activating transient KCa currents and single KCa NKA through cGMP and protein kinase G (PKG) and glu-
channels in myocytes in contact with astrocytes resulting in tamate regulates CO through mGluRs.263,265 NKA has been
dilation of the vessel, increase in blood flow, and subsequent estimated to be responsible for nearly 50% of the cellular
increased availability of energy sources when needed.261-263 ATP hydrolysis linking cellular sodium regulation and energy
While glucose has been considered the obligatory energy sub- metabolism in the CNS. Decreased NKA activity results in
strate in adult brains via oxidative metabolism, other substrates energy deficiency and has been associated with neurodegen-
from the blood (ketones, lactate, etc.) are also used as energy erative diseases.265-267,269-273 Upregulation or downregulation
sources and may be preferred and are transported into both of astrocyte production of CO to affect sodium homeostasis
neurons and astrocytes. Nonoxidative metabolism for energy and energy levels of neurons needs further evaluation as the
production may be important as well.264-266 The metabolism of interactions between astrocytes, glutamate, and CO directly
glucose to CO2 and water may or may not result through gly- affects neurons, CNS health, and pathologies of the CNS.
colysis, the pentose phosphate pathway, and/or glycogenolysis
as metabolic intermediates can also be oxidized as an energy Release of glutamate from astrocyte
source (i.e. lactate, pyruvate, glutamate, or acetate). Ca2+-dependent exocytosis
Glycogen, an energy substrate found predominantely Exocytosis of glutamate, one of the mechanisms of astrocytic
in astrocytes, is broken down to lactate and is affected by glutamate release, is largely dependent on soluble N-ethylma-
neurotransmitters and glucose concentration and provides leimide-sensitive-factor attachment protein receptor proteins
some neuroprotection during hypoglycemia and high levels (regulators of exocytosis) and is Ca2+-dependent. Extracellular
of CNS activity. Lactate is considered to be neuroprotective signaling molecules result in an increase in Ca2+ concentra-
and may be the preferred CNS energy substrate. Interestingly, tion in the cytosol and, triggered by an increase of cytosolic
glutamate stimulated CO production by astrocytes with intact Ca2+ (mainly from endoplasmic reticulum stores), exocytosis
heme-oxygenase 2 also affects L-lactate levels in astrocytes of glutamate results with the merger of gliosignal-containing
suggesting an association between L-lactate and heme oxy- vesicles with the plasma membrane and membrane associated
genase neuroprotective systems. The cell specific metabolic molecules.274-278 Released astrocytic glutamate reacts with
profile of astrocytes is different from that of neurons and receptors on synaptic terminals and excitability of neurons
there are different expressions of enzymes that regulate cell is seen. Mitochondria have a Ca2+ uniporter that transports
metabolism including glycogenolysis and glycolysis. Intercel- Ca2+ into the mitochondrial matrix when cytosolic Ca2+ is
lular lactate shuttles transferring lactate from lactate-producing greater than about 0.5 µM which, when blocked, increases
cells to lactate-consuming cells exist between astrocytes and cytosolic Ca2+ and glutamate release.241,279 CO decreases the
neurons – a lactate gradient from astrocytes to neurons allows activity of L- and T-type Ca2+ channels, probably affects Ca2+
for a carrier-mediated lactate flux from astrocytes to neurons signaling between endoplasmic reticulum and mitochondria,
and astrocyte-derived lactate can be used as an energy sub- regulates the mitochondrial calcium uniporter and regulates
strate for neurons.267,268 Anaerobic glycolysis results when mitochondrial Ca2+ concentrations.241-243 Ca2+ regulation by
pyruvate is acted on by lactate dehydrogenase to form lactate CO, therefore, affects Ca2+-dependent exocytosis and requires
and aerobic glycolysis when a cell specific gene expression further study.
profile that affects conversion of pyruvate to lactate as op-
posed to pyruvate being used in the TCA cycle. Transport of Intracellular calcium concentration
glucose across the blood brain barrier is ten times higher for Astrocytes, activated during physiological functioning of the
glucose than for lactate and astrocytes (in an activity dependent CNS, release glutamate in response to an increase in Ca2+, but
manner) determines CNS lactate formation by an uncoupling Ca2+ concentration in astrocytes does not result in on/off re-
between glycolysis and the TCA cycle. Studies are needed to sponses but rather in different and graded functions depending
further define the role of lactate in neuroprotection, effect of on the need of the cell - the type of neuronal input is important
CO on production of lactate and other metabolic substrates in to the type of astrocytic Ca2+ response. Reactions vary in the
astrocytes, use of lactate as an energy substrate by astrocytes different organelles. Ca2+ enters the cell through Ca2+ chan-
and neurons, transport of lactate from astrocytes to neurons, nels in the plasma membrane or store-operated Ca2+ channels.
and metabolism of various metabolic substrates to lactate. Sources include the extracellular space and the endoplasmic
reticulum/sarcoplasma reticulum. Mitochondria Ca2+ uptake is
Uptake of glutamate by astrocyte efficient and is mainly via a mitochondria Ca2+ uniporter (MCU
Failure of sodium homeostasis, due to reduced ATP, results or CCDC109A).278,279 Ca2+ crosstalk with the plasma membrane
in extra- and intracellular changes of potassium, calcium, and is important for cellular functions. Within mitochondria, Ca2+
protons and, therefore, changes in excitotoxicity. Astrocyte activates three dehydrogenases (pyruvate dehydrogenase, oxo-
metabolism and sodium homeostasis is dependent on glutamate glutarate dehydrogenase, and isocitrate dehydrogenase) in the
uptake and is critical to maintaining sodium homeostasis and mitochondrial matrix, stimulates production of ROS, results
energy levels of surrounding neurons. A major determinant of in opening of mitochondrial permeability transition pores and
uptake of glutamate by astrocytes is the transmembrane Na+ possibly regulates Fl-Fo ATP synthase.280-283 Efflux of the ion
gradient controlled by NaK-ATPase (NKA). The latter has from mitochondria is primarily determined by Na+-dependent
three subunits – α, β, and γ with 4 isoforms of the α subunit. and Na+-independent pathways. Astrocyte mitochondrial
Astrocytes express α1 and α2 subunits and, in the brain, the Na+-Ca2+ exchanger is important for store-operated Ca2+ en-
try indicating communication between mitochondria and the are needed for brain development through regulation of ex-
plasma membrane. CO is essential to the observed effects of tracellular glutamate concentrations, and modify metabolic
intracellular Ca2+ concentration on cellular functions – CO communications between neurons and astrocytes. The major-
stimulates astrocytic mitochondrial biogenesis via L-type Ca2+ ity of these physiologic processes (neurovascular coupling,
channel-mediated peroxisome proliferator-activated receptor- excitatory signaling, Na+/Ca2+ exchangers, Na+/K+ ATPase,
gamma coactivator -1alpha/estrogen-related receptor α activa- glycogen phosphorylase/glycogen synthase, mitochondria/
tion and through potentiation of L-type Ca2+ channel activity oxidative phosphorylation, glycolytic enzymes/glycolysis,
increases hypoxia-inducing factor-1α-independent vascular and glutamate/metabolic pathways) are mediated by GLT-1
endothelial growth factor expression via an AMP-dependent and GLAST (EAAT1 and EAAT2) – astroglial glutamate
protein kinaseα/sirtuin1-mediated peroxisome proliferator- transporters – and co-localize with, form interactions with,
activated receptor-gamma coactivator -1alpha/estrogen-related and couple to energy-generating systems. Primary functions
receptor α axis.283,284 Other effects of CO on intracellular Ca2+ of EAATs (sodium-dependent glutamate transporters) include
need further evaluation. maintaining extracellular glutamate concentration in the low
micromolar range which allows glutamate to be used as a
Potassium channels signaling molecule while preventing cytotoxic effects and
Astrocytes may serve as excitatory interneurons that affect syn- controlling antioxidant defenses and metabolic roles of trans-
chrony of a set of neurons.45,47 Modulation of excitability and ported substrates. Binding of glutamate is rapid and buffering
synchronization of neuronal activity and network oscillations after entry into the extracellular space results. Responses are
through the effect of K+ may be partially regulated through dynamic and depend on the location of the transporters. Uptake
Ca2+-dependent release of glutamate (activate extrasynaptic of glutamate is via co-transport of three sodium ions and one
NMDA receptors) that depends on K+. Extracellular K+ con- proton with counter-transport of one potassium ion. Energy is
centration and astrocyte depolarization also affect glutamate released and active transport of glutamate results. If extracel-
uptake through glutamate transporters – inverse glutamate lular glutamate uptake by astrocytes is reduced, excitotoxic-
uptake and vesicular glutamate release may affect synchrony ity occurs. After uptake, glutamate is directed into different
of neurons and is affected by K+ buffering by astrocytes.285,286 enzymatic pathways and may result in energy production and
Uptake of excess extracellular K+ released during neuronal glutamine production. Activity of EAATs is closely coupled
discharge is important to the regulation of extracellular K+ that to glutamine release by astrocytes.301-305
regulates neuron membrane potential and subsequent excitabil- Astrocyte GLAST and GLT-1 are responsible for the clearing
ity. Diverse astrocyte K+ channels mediate these K+ currents. of extracellular glutamate. In a hippocampal astrocyte culture
Astrocytes express various K+ channels that depend on CNS from adult and aged rats, decreases in GLAST and GLT-1 were
development and region of the brain with specific subcellular associated with decreases of nuclear factor E-2 related factor
types that include inward rectifying K+ (Kir) channels (Kir4.1, 2 (Nrf2) – regulates the transcription of HO-1 and, therefore,
Kir5.1, and Kir6.1 present in astrocytes), two-pore-domain CO production which probably mediates neuroprotection.306-309
K+ (K2P) channels (TASK1, TREK2, TREK1, and TWIK1), Further studies are needed to evaluate the relationship between
Ca2+ activated K+ channels, and Kv channels (Kv1 to Kv12 Nrf2, HO-1, CO, GLAST and GLT-1.
which include channels affected delayed rectifier (KDR) and
transient (KA) currents).285-290 The channels are involved in Glutamate-gated ion channel receptors
processes that depend on transmembrane voltage, i.e., Kir4.1 Astrocyte glutamate signaling follows binding of glutamate
sets the resting potential of astrocytes and is responsible for to iGluRs and/or mGluRs and can lead to calcium signaling
the large inward currents recorded at negative membrane po- and subsequent glial excitability. Although the former is
tentials, TASK1 may inhibit cellular swelling under ischemic ubiquitously expressed in all neural cell types, iGluR subunit
conditions,291 BK channels depend on membrane potential and composition (18 iGluR receptor subunits) and subtypes differ
intracellular Ca2+ concentration, and Kv channels are expressed between species, CNS cell types and brain areas, and change
perinatally. Astrocyte K+ conductance is dominated by the Kir during development. Presence is not all or none, but rather
channels.292-297 quantitative, and developmental patterns are unique. A primary
Outside of the CNS, CO interacts with K+ channels.298,299 In function is sensing and responding to neuronal release of glu-
vascular smooth muscle K (Ca) channels are activated and a tamate – differences exist between astrocytes, types of iGluRs
specific target of CO is the histidine residue. Activation of ATP- present, area of the brain, and other biochemical reactions
sensitive K+ channels results in the peripheral antinociceptive present in the area. Heterogeneity in the function of iGluRs
effect of the HO/CO pathway. CO inhibits the voltage-gated K+ may result from differential expression of subtypes. AMPAR
currents in the medulloblastoma cell line DAOY and reverses are mainly responsible for fast excitatory synaptic transmis-
the oxidant-induced increase in K+ activity.300 CO results in sion and synaptic plasticity, NMDAR for excitatory synaptic
inhibition of recombinant Kv2.1 expressed in HEK293 cells. transmission, plasticity, and excitotoxicity, and kainate recep-
These K+ channel effects have not been studied in astrocytes tors for regulating activity of synaptic networks and synaptic
and deserve further evaluation. plasticity in the hippocampus and sensory cortex, but delta
receptors (belong to the iGluR family because of sequence
Sodium dependent glutamate transporters homology) function as ion channels only after interaction with
Astrocytic, not neuronal, glutamate transporters are impor- other types of membrane proteins.310-317
tant to maintaining extracellular glutamate concentrations, Apolipoprotein E (ApoE) affects these iGluR functions.
ApoE, the major apolipoprotein in the CNS interaction with

strate utilization in the brain of newborn piglets undergoing
other types of membrane proteins (predominantly synthesized
deep hypothermic circulatory arrest.331 Loss of CO produc-
by astrocytes), reduces the level of extracellular glutamate and
tion and pial arteriolar dilation following astrocyte injury
iGluR activation and, possibly, glutamate induced excitotoxic
suggests that astrocytes may employ CO as a gasotransmitter
damage and protects astrocytes from hypoxia and glutamate-
for glutamatergic cerebrovascular dilation.320 Inhibition of
induced apoptosis. Nrf2 is increased in the presence of ApoE.
synaptosomal glutamate uptake by CO in a time-, dose-, and
The downstream target of Nrf2, heme oxygenase (and, there-
temperature-dependent manner was shown in the striatum and
fore, CO production), is essential for cytoprotection.318-323
hippocampus.332 In newborn pigs, the astrocyte component
Studies have not been done evaluating the effect of ApoE on
of the neurovascular unit is responsible for the vasodilation
astrocyte glutamate and iGluR activation, Nrf2 production, and
response of pial arterioles to topically applied glutamate via
upregulation of heme oxygenase and CO production and their
iGluRs functionally liked to activation of constitutive heme
interrelationships and are needed to further define the role of
oxygenase.333 Glutamate elevates Ca2+ (i) in astrocytes lead-
upregulation of CO by ApoE on neuroprotection.
ing to Ca2+- and calmodulin-dependent HO-2 activation, and
CO production.334 These and other effects of CO on astrocyte
Calcium permeability of α-amino-3-hydroxy-5-methyl-4-
homeostasis of glutamate requires further evaluation and delin-
isoxazoleproprionic acid receptors and GluA2
eation. Results may lead to a simpler and better understanding
Subunit composition of AMPA receptors is dynamic and
of the role of CO in normal and abnormal astrocyte/glutamate
changing. Their Ca2+ permeability and resulting action poten-
interactions and result in medical interventions that limit or
tials are reflected in the output of neurons, normal synaptic
cure disease processes in the CNS.
functions and disease. Functional differences result in differ-
ences in excitatory signaling. Ca2+ permeability is related to
the GluA2 subunit which may be subjected to RNA editing Author contributions
by the ADAR2 enzyme – edited GluA2 subunits render the The author completed the manuscript independently.
AMPA receptor impermeable to Ca2+. Change in number of Conflicts of interest
The author has no conflicts of interest.
AMPA receptors and GluA2 inclusion results in a change in Financial support
AMPA receptor Ca2+ permeability and, therefore, synaptic None.
transmission and intracellular signaling. GluA2 mRNA and Copyright license agreement
The Copyright License Agreement has been signed by the author
GluA2 subunit expression are downregulated in neurons prior
before publication.
to cell death. The “GluA2 hypothesis” suggests that reduction Plagiarism check
of GluA2 results in more Ca2+ influx through newly synthe- Checked twice by iThenticate.
sized AMPA receptors and, thereby, results in neurotoxicity Peer review
Externally peer reviewed.
secondary to glutamate. Unedited GluA2 results in AMPA Open access statement
receptors that are permeable to Ca2+. Blocking the formation This is an open access journal, and articles are distributed under
of GluA2-less receptors, blocking GluA2-less receptors, and the terms of the Creative Commons Attribution-NonCommercial-
blocking of resulting apoptosis are approaches used to reduce ShareAlike 4.0 License, which allows others to remix, tweak, and
build upon the work non-commercially, as long as appropriate credit
neurotoxicity. As in neurons, Ca2+ influx results in astrocytic is given and the new creations are licensed under the identical terms.
Ca2+ signaling. AMPA-evoked Ca2+ influx into astrocytes has
been associated with a weak expression of GluA2.324-330 CO
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Accepted: February 15, 2019

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Neurointegrity and europhysiology: astrocyte,

*Correspondence to: Vicki L. Mahan, MD, [email protected].

of Ca2+ 41,42 and the astroglial cradle (formed by perisynaptic

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ApoE, the major apolipoprotein in the CNS interaction with

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