Cell. Mol. Life Sci.
DOI 10.1007/s00018-013-1484-0
Review
Changes in the expression of the glutamate transporter
EAAT3/EAAC1 in health and disease
Massimiliano G. Bianchi · Donatella Bardelli ·
Martina Chiu · Ovidio Bussolati 
Received: 9 August 2013 / Revised: 17 September 2013 / Accepted: 19 September 2013
© Springer Basel 2013
Abstract Excitatory amino acid transporters (EAATs)
are high-affinity Na+-dependent carriers of major impor-
tance in maintaining glutamate homeostasis in the cen-
tral nervous system. EAAT3, the human counterpart of
the rodent excitatory amino acid carrier 1 (EAAC1), is
encoded by the SLC1A1 gene. EAAT3/EAAC1 is ubiqui-
tously expressed in the brain, mostly in neurons but also in
other cell types, such as oligodendrocyte precursors. While
most of the glutamate released in the synapses is taken up
by the “glial-type” EAATs, EAAT2 (GLT-1 in rodents) and
EAAT1 (GLAST), the functional role of EAAT3/EAAC1
is related to the subtle regulation of glutamatergic trans-
mission. Moreover, because it can also transport cysteine,
EAAT3/EAAC1 is believed to be important for the syn-
thesis of intracellular glutathione and subsequent protec-
tion from oxidative stress. In contrast to other EAATs,
EAAT3/EAAC1 is mostly intracellular, and several mecha-
nisms have been described for the rapid regulation of the
membrane trafficking of the transporter. Moreover, the
carrier interacts with several proteins, and this interaction
modulates transport activity. Much less is known about
the slow regulatory mechanisms acting on the expression
of the transporter, although several recent reports have
identified changes in EAAT3/EAAC1 protein level and
activity related to modulation of its expression at the gene
level. Moreover, EAAT3/EAAC1 expression is altered in
M. G. Bianchi · D. Bardelli · M. Chiu · O. Bussolati (*) 
Unit of General Pathology, Department of Biomedical,
Biotechnological and Translational Sciences (SBiBiT),
University of Parma, Via Volturno 39, 43125 Parma, Italy
e-mail: ovidio.bussolati@unipr.it
M. G. Bianchi 
Unit of Occupational Medicine, Department of Clinical
and Experimental Medicine, University of Parma, Parma, Italy
Cellular and Molecular Life Sciences
pathological conditions, such as hypoxia/ischemia, mul-
tiple sclerosis, schizophrenia, and epilepsy. This review
summarizes these results and provides an overall picture
of changes in EAAT3/EAAC1 expression in health and
disease.
Keywords EAAC1 · EAAT3 · Glutamate · Oxidative
stress · Glutathione · Retinoids
Introduction
EAAT3, the human counterpart of the EAAC1 rodent trans-
porter, is a member of the EAAT family of high-affinity,
sodium-dependent glutamate carriers encoded by genes
of the SLC1 family [1–3]. EAAT3/EAAC1 is coded by
SLC1A1/Slc1a1 and was the first sodium-dependent mam-
malian amino acid transporter to be cloned [4]. When
studying the activity of EAAT3/EAAC1 in cultured human
fibroblasts before its cloning, early researchers demon-
strated that the transporter can accept the D isomer of
aspartate but not the D isomer of glutamate [5]. This stere-
oselective anomaly has been consistently confirmed for all
the transporters for anionic amino acids of the SLC1 family
and is one of the functional hallmarks of EAAT carriers.
Like other EAAT carriers, EAAT3/EAAC1 uses the
transmembrane gradients of Na+, K+, and H+ electrochem-
ical potentials as the driving force to accumulate glutamate
from the extracellular space [6, 7]. Glutamate is co-trans-
ported with 3 Na+ and 1 H+, while 1 K+ is extruded in the
same cycle, ensuring the electrogenicity of the transport
cycle and the formation of a high transmembrane gradient
of the transported substrates.
The expected molecular weight of the transporter is
64 kDa, but electrophoretic migration yields higher values,
13

ascribed to a high degree of glycosylation. Moreover, West-
ern-blot experiments have demonstrated high-molecular-
weight bands, referred to as trimers of the transporter. In
fact, trimers are thought to constitute the functional unit of
EAAT3/EAAC1 in situ [8, 9]. Although experimental data
on the carrier structure are incomplete, EAATs have 8–10
transmembrane domains, with glycosylation sites in the
extracellular loop between TM3 and TM4 and several puta-
tive intracellular consensus phosphorylation sites [10].
EAAT3/EAAC1 is expressed not only in the central
nervous system (CNS) but also in Schwann cells [11].
Moreover, the carrier is also expressed in the intestine and
kidney, where it accounts for the absorption/reabsorption
of dicarboxylic amino acids, and in many other tissues.
Defective expression of functional EAAT3/EAAC1 results
in dicarboxylic aminoaciduria (OMIM222730) [12]. In
the CNS, of the five EAATs characterized so far, EAAT4
[13] and EAAT5 [14] are highly expressed in cerebellar
Purkinje cells and in retinal photoreceptors and bipolar
cells, respectively. In contrast, EAAT1 and EAAT2 pre-
dominately have a glial distribution, while EAAT3/EAAC1
is highly expressed in glutamatergic and GABAergic neu-
rons [15], especially in somata and dendrites (with par-
ticular abundance in the neck of dendritic spines [16]) but
not in synaptic terminals of axons or spine heads [16–18].
Other neuronal populations express EAAT3/EAAC1, such
as dopaminergic neurons; these neurons are very sensi-
tive to carrier dysfunction [19, 20] or inhibition [21].
EAAT3/EAAC1 is also expressed in cells of glial origin,
such as in subsets of oligodendrocytes [22], in immature
oligodendrocytes [23], and in oligodendrocyte progenitor
cells [24]. An isolated report describes EAAT3/EAAC1
expression also in microglial cells after traumatic brain
injury [25]. Mature astrocytes are generally believed to be
EAAT3/EAAC1-negative, but it should be noted that astro-
glial tumor cells, such as rat C6 glioma cells and several
human glioma cell models, express the transporter [26]. At
variance with other EAAT transporters [27, 28], the expres-
sion of EAAT3/EAAC1 is mainly intracellular [22, 29,
30]; only a minor portion of the carriers are targeted to the
plasma membrane under control conditions, while most are
associated with cytoplasmic vesicles [15, 16].
This peculiar distribution has relevant consequences for
the regulation of transporter activity. In cells of both nerv-
ous and non-nervous origin, EAAT3/EAAC1 activity is
modulated by post-translational mechanisms that rapidly
modify its trafficking and abundance on the plasma mem-
brane. EAAT3/EAAC1 abundance on the plasma mem-
brane is readily enhanced upon PKC activation [31] or
stimulation with PDGF [32]. Several PKC enzymes may
be involved in these regulatory effects at different levels
[31–34]. In addition, other kinases have been implicated in
the regulation of EAAT3/EAAC1 trafficking and activity
13
M. G. Bianchi et al.
in Xenopus oocytes injected with the transporter cDNA,
including phosphatidylinositol-3 (PI3)-kinase, the phosph-
oinositide-dependent kinase PDK1, the serum- and gluco-
corticoid-inducible kinase SGK1, and the phosphatidylino-
sitol-3-phosphate-5-kinase PIKfyve [35]. Interestingly, the
gene encoding PIKfyve is associated with schizophrenia
and the mutant form expressed in patients seems to exert
a dominant-negative effect on EAAT3 trafficking in Xeno-
pus oocytes [36]. In the same experimental model, mTOR
increases EAAT3/EAAC1 activity [37], which, instead, is
decreased by the mTOR inhibitor AMPK [38].
These effects may be due to a direct interaction between
EAAT3/EAAC1 and the kinase or, more often, to changes
in the interaction between the transporter and several intra-
cellular proteins, such as the endoplasmic reticulum pro-
teins addicsin/glutamate transporter-associated protein
3-18 (GTRAP3-18, [39]) and reticulon (RTN2B, [40]),
which are believed to play opposite regulatory roles in
the membrane-targeting of the transporter [41, 42]. Inter-
estingly, the gene for GTRAP3-18, which is a negative
modulator of EAAT3/EAAC1 activity, maps to human
chromosome 3p14, a susceptibility locus for cancer and
epilepsy [43]. GTRAP3-18 is negatively regulated by ADP-
ribosylation factor-like 6-interacting protein 1 (Ar16ip1),
which causes a decreased interaction between GTRAP3-
18 and EAAT3/EAAC1 in neurons [44]. Moreover,
EAAT3/EAAC1 trafficking involves several steps depend-
ent on Rab11 [45], SNAP-23 (a SNARE protein) [46], and
caveolin-1 [47], although evidence for a direct interac-
tion between the transporter and these proteins is lacking.
The δ-opioid receptor is a G-protein that also modulates
EAAT3/EAAC1 activity [48]. EAAT3/EAAC1 also inter-
acts with the cytoskeletal protein α-adducin [49], which is
particularly abundant in dendritic spines [50], although, in
this case, the functional implications of the interaction have
not been defined.
Compared to these multiple sites of regulation at the pro-
tein level, the characterization of mechanisms modulating
EAAT3/EAAC1 synthesis at the transcriptional level has
been much slower. This review aims to recount the infor-
mation available on this subject as well as on pathologi-
cal situations in which the expression of EAAT3/EAAC1
is altered. Before examining the regulatory mechanisms,
a brief summary on the physiological role of EAAT3 is
discussed.
EAAT3/EAAC1 functions in physiology and pathology
In general, the activity of EAAT transporters is consid-
ered the main mechanism responsible for the termination
of glutamatergic transmission. As such, EAAT transport-
ers are believed to be important factors for the prevention
Changes in the expression of the glutamate transporter
of excitotoxic damage, i.e., neuronal loss due to excessive
influx of calcium mediated by the overstimulation of glu-
tamate receptors of the NMDA and AMPA/kainate classes.
However, the roles of the three most important EAATs,
EAAT1, EAAT2, and EAAT3/EAAC1, are thought to be
diverse [51]. This is well exemplified by experiments with
knock-out animals. Whereas the knock-outs for GLAST
(the rodent counterpart of EAAT1) and GLT-1 (the rodent
EAAT2) exhibit early signs of severe excitotoxic damage
[52], the knock-out for EAAT3/EAAC1 has an apparently
normal development [53]. However, these animals present
symptoms of precocious neurodegeneration and subtle neu-
rologic damage, associated with cell loss in the cerebral
cortex, increased aggressiveness and impaired self-groom-
ing [54]. In particular, EAAT3/EAAC1-deficient mice
exhibit spatial learning/memory dysfunction, loss of dopa-
minergic neurons in the substantia nigra, and movement
disorders; these disturbances typically appear at senescence
[20, 54] but have also been reported in young animals [55].
Moreover, patients affected by dicarboxylic aminoaciduria
also display hints of neurologic damage [12, 56].
The prevalent opinion is that the basic mechanism
for termination of glutamatergic transmission resides
in EAAT1 and EAAT2 function. Consistent with this
hypothesis, these transporters are endowed with higher
affinity for substrates than EAAT3/EAAC1 and are local-
ized in glial cell processes close to synaptic clefts, while
EAAT3/EAAC1 is mostly extra-synaptic [16]. Therefore,
EAAT3/EAAC1 may be important in situations where glu-
tamate spills out from the synaptic zone or reaches abnor-
mally high extracellular concentrations, for example under
ischemic conditions (see below). However, EAAT3/EAAC1
may play an important role in glutamatergic termination in
areas such as the hippocampus, where most synapses are
not closely surrounded by astrocytic processes [57]. How-
ever, EAAT3/EAAC1 is far less abundant than EAAT2 also
in these regions [18].
Although glutamate uptake represents the best-charac-
terized activity of the carrier, EAAT3/EAAC1 also trans-
ports cysteine [58, 59] and may provide the majority of the
influx of the amino acid in neurons [60]. Through cysteine
uptake, EAAT3/EAAC1 contributes to the intracellular
synthesis of glutathione [59, 61], one of the most impor-
tant intracellular antioxidants. EAAT3/EAAC1-mediated
uptake may be the major contributor of cysteine to glu-
tathione synthesis, because the knock-out mouse for xCT,
the catalytic subunit of the sodium-independent transport
system for cystine, is apparently normal and shows no
changes in brain glutathione content [62]. Indeed, the mod-
ulation of EAAT3/EAAC1 activity correlates with neuronal
glutathione content [41]. Further, the impaired Rab11-
dependent trafficking of EAAT3/EAAC1 is associated with
enhanced sensitivity to oxidative stress in a murine model
of Huntington disease [63]. The mouse knocked-out for
EAAT3/EAAC1, which presents a decreased glutathione
content in neurons and early onset brain aging, exhibits
significant biochemical and functional improvements if
treated with the antioxidant N-acetyl-cysteine [64].
The high expression of EAAT3/EAAC1 in GABAergic
neurons supports its role in the metabolic fueling of GABA
synthesis. This role is also supported by the increase in par-
oxysmal activity in animals treated with antisense oligonu-
cleotides that hinder transporter expression (see below and
[65]).
In addition, EAAT3/EAAC1 also has an impor-
tant function in the regulation of synaptic transmission.
EAAT3/EAAC1 is involved in long-term potentiation and,
hence, in memory and higher cerebral functions [66–69].
Acute regulation of EAAT3/EAAC1 membrane expression
and activity by volatile anesthetics [70, 71] and carbamaz-
epine [72] may represent examples of pharmacological
modulation of these mechanisms.
Regulatory mechanisms at the gene and protein levels
The expression of EAAT3/EAAC1 varies during brain
development [73, 74], and the transporter is expressed
before EAAT1 and EAAT2 both in vitro [75] and in vivo
[73]. Early expression suggests a role for EAAT3/EAAC1
in neuroprotection of CNS cells during brain development.
Moreover, because GABAergic neurons reach maturation
before excitatory glutamatergic cells in the hippocam-
pus, the early expression of EAAT3/EAAC1 may play an
important role in developing the glutamatergic neuronal
network [76]. These data are consistent with recent evi-
dence showing that the EAATs are differentially regulated
during the differentiation of human astroglial progenitors
[77]. In particular, EAAT3/EAAC1 is more expressed than
EAAT1 and EAAT2 in A2B5-positive cells and decreases
upon differentiation to the astrocytic phenotype. Interest-
ingly, early precursors of the oligodendroglial cell lineage
are A2B5 positive [78].
Notwithstanding these data, studies focused on the
modulation of the SLC1A1 gene under differentiating stim-
uli are lacking. In Hs683 human oligodendroglioma cells
valproic acid (VPA) and trichostatin A, two inhibitors of
histone deacetylases (HDACs), strongly increase SLC1A1
mRNA as well as EAAT3/EAAC1 protein expression and
transport activity [79]. In the same model, VPA signifi-
cantly also enhances the expression of PDGFRA, an early
marker of oligodendrocyte precursors cells (OPCs), while it
does not affect the expression of either TUBBIII or GFAP,
markers of neuronal and glial cells, respectively. VPA is a
well-known differentiating agent, and its effects on the dif-
ferentiation of CNS cells have been repeatedly reported. In
13

particular, VPA promotes neuronal differentiation of multi-
potent adult neural progenitor cells and influences the tim-
ing of oligodendrocyte differentiation in the developing rat
brain [80, 81].
In another model of immature CNS cells, the rat glioma
cell line C6, the differentiating agent all–trans retinoic
acid (ATRA) markedly increases EAAT3/EAAC1 expres-
sion at both the mRNA and protein levels. ATRA effect
is specific for the Slc1a1 gene because it does not affect
either GLT-1 (Slc1a2) or GLAST (Slc1a3) protein levels
[82]. RAR-specific but not RXR-specific inhibitors prevent
EAAT3/EAAC1 induction after ATRA treatment, while the
RAR-specific agonist Am80 (tamibarotene, retinobenzoic
acid) mimics the ATRA effect. Conversely, EAAT3/EAAC1
induction is prevented by Rarbeta silencing, demonstrating
that the ATRA effect on EAAT3/EAAC1 strictly depends
upon the RARβ receptor [83]. A consensus site for RARβ
has been identified in the rat Slc1a1 promoter but not in the
human SLC1A1 promoter region [83]. Along with Slc1a1
induction, the expression of the oligodendrocytic marker
Plp1 is also enhanced by ATRA in C6 cells [82, 84], sug-
gesting that retinoids may be involved in the activation of
the oligodendrocytic differentiation pathway.
Soon after the cloning of the transporter, increased
expression of EAAT3/EAAC1 was reported in bovine
NBL-1 renal epithelial cells incubated under hypertonic
conditions. Incubation of these cells in medium supple-
mented with 200 mM sucrose leads to a marked increase in
EAAT3/EAAC1 mRNA and protein, as well as to the stim-
ulation of anionic amino acid transport [85]. Although it
has not yet been demonstrated, it is likely that, as with other
amino acid transporters [86], EAAT3/EAAC1 induction
also involves the activation of the osmosensitive transcrip-
tion factor NFAT5/TonEBP [87]. Incubation in the pres-
ence of tunicamycin, an inhibitor of protein glycosylation
that triggers endoplasmic reticulum (ER) stress, increases
EAAT3/EAAC1 mRNA and protein [88]. In contrast,
incubation of NBL-1 cells in the absence of amino acids,
a condition that promotes the expression of other sodium-
dependent transporters, such as SNAT2 [89], stimulates
aspartate transport but not EAAT3/EAAC1 expression [90].
Thus, it seems that in NBL-1 renal epithelial cells Slc1a1 is
induced by several (but not all) forms of stress associated
with increased protein unfolding and ER stress. Unfortu-
nately, these experiments have not been repeated in CNS-
derived cell models.
Ma et al. [91] have found that a binding sequence for the
regulatory factor X1 (RFX1) exists in the promoter region
of SLC1A1, but not in the promoters of SLC1A2 (encod-
ing EAAT2) and SLC1A3 (encoding EAAT1). RFX pro-
teins are transcription factors that bind to X-boxes of DNA
sequences. In the mouse brain, RFX1 is expressed from
the embryonic state (E15) to adulthood, and its knock-out
13
M. G. Bianchi et al.
is lethal in the early embryonic state, suggesting an indis-
pensable role in brain development [92]. In rats and mice,
RFX1 is highly expressed in several regions of the brain,
such as the hippocampus, the cerebellum (Purkinje cells),
and the olfactory bulb, with localization in the nuclei
of neurons and microglial cells but not in the nuclei of
astrocytes [93]. In the study by Feng and Zuo [93], 24 h
after transfection of C6 glioma cells with human RFX1,
EAAT3/EAAC1 expression increased by 60 % and trans-
porter activity increased by 40 %. Conversely, knock-
down of RFX1 expression by antisense oligonucleotides
decreased EAAT3/EAAC1 expression in rat cortical neu-
rons in culture. Moreover, transfection with RFX1 stimu-
lated the transcriptional activity of the SLC1A1 promoter in
both rat glioma C6 cells and human neuroblastoma SHSY-
5Y cells. Thus, although SLC1A1 mRNA was not directly
measured in that study, these data suggest that the increase
in EAAT3/EAAC1 expression was due to the interaction of
RFX1 with the promoter [93]. However, the natural activa-
tors of RFX1 are not known, and it is difficult to assess its
physiological role.
Although most of the previous studies on
EAAT3/EAAC1 function have focused on its role in the
regulation of glutamate homeostasis, accumulating evi-
dence suggests that the carrier plays an essential function in
controlling cell redox potential (see above). Astrocytes sup-
port neuronal antioxidant capacity by releasing glutathione,
the most important anti-oxidant agent in the CNS, which
is cleaved to cysteine in brain extracellular space [94].
Free cysteine supply is the limiting step for glutathione
synthesis, and neuronal cysteine influx depends upon
EAAT3/EAAC1 activity [95]. The activation of the nuclear
factor erythroid 2-related factor 2 (Nrf2)-antioxidant
responsive element (ARE) pathway by oxidative stress pro-
motes not only glutathione release from astrocytes but also
the transcriptional regulation of neuronal EAAT3/EAAC1
both in vitro and in vivo [95]. Moreover, Nrf2-depend-
ent overexpression of EAAT3/EAAC1 protein is associ-
ated with an increase in neuronal glutathione content, and
these effects are abrogated in mice genetically deficient
in either Nrf2 or EAAT3/EAAC1. Selective overexpres-
sion of Nrf2 in brain neurons by lentiviral gene transfer
is sufficient to up-regulate both neuronal EAAT3/EAAC1
protein and glutathione content. These findings support a
mechanism whereby Nrf2 activation can coordinate astro-
cyte glutathione release with neuronal glutathione syn-
thesis through transcriptional up-regulation of neuronal
EAAT3/EAAC1 expression. EAAT3/EAAC1-mediated
cysteine uptake has also recently been implicated in the
increased neuronal glutathione content of mice treated with
caffeine or uric acid [96], although the underlying mech-
anism has not yet been elucidated. Interestingly, recent
contributions demonstrate that fumarates can activate
Changes in the expression of the glutamate transporter
Nrf2-dependent responses and thereby ameliorate the dis-
ease course of experimental autoimmune encephalomyeli-
tis (EAE), a rodent model of multiple sclerosis (MS) [97,
98]. The protective effect of fumarates is associated with
improved preservation of myelin and neurons. Unfortu-
nately, no investigation was performed on possible changes
in EAAT3/EAAC1 induced by fumarates in these models.
In a report by Molteni et al. [99], EAAT3/EAAC1 was
up-regulated in parallel with glutamate NMDA receptor
subunits after chronic periods of exercise, providing further
support for a functional role of the transporter in the modu-
lation of glutamatergic transmission.
Overall, these data suggest that the transcriptional regu-
lation of EAAT3/EAAC1 expression has peculiar features
because most of the reported mechanisms specifically affect
the transporter, which, conversely, appears insensitive to
well-characterized inducers of EAAT1 and EAAT2 [100,
101]. Similarly, studies on knock-out models for glutamate
receptors demonstrate that EAAT1 and EAAT2 expres-
sion is lower in mGluR3−/− mice, while EAAT3/EAAC1
is decreased in mGluR2−/− animals [102]. However,
examples of a parallel regulation of EAAT1, EAAT2, and
EAAT3/EAAC1 proteins have been also reported [103].
Pathological conditions involving changes
in EAAT3/EAAC1 expression
Alterations in EAAT3/EAAC1 have been associated with
several pathological conditions. In particular, there is a
strong association between single-nucleotide polymor-
phisms (SNPs) in SLC1A1 and obsessive–compulsive dis-
order [104–107], but these polymorphisms seem more
correlated with changes in transporter function than with
its expression. Dicarboxylic aminoaciduria is a Mendelian
disorder (OMIM 222730) where EAAT3/EAAC1 function
is defective due to the expression of a mutant, functionally
impaired transporter that is also scarcely sorted to the cell
membrane [12]. Clear-cut, although contrasting, changes
in EAAT3/EAAC1 expression have been described in Alz-
heimer’s disease (AD). Results in mouse models of AD
are conflicting. Schallier et al. [108] reported an increase
in EAAT3/EAAC1 expression (although overwhelmed
by a concomitant decrease in GLT-1 and GLAST levels)
in AβPP23 mice, while a decrease in the expression of all
three glutamate transporters has been reported by Cas-
sano et al. [109] in triple transgenic (3×Tg) AD mice. In
humans, aberrant intracellular accumulation of a detergent
insoluble EAAT3/EAAC1 was described in hippocampal
neurons of AD patients, although overall cortical expres-
sion of the transporter was comparable to controls, suggest-
ing a defect in transporter processing rather than synthesis
[110].
Four conditions in which alterations in EAAT3/EAAC1
expression have been identified will be discussed: hypoxia/
ischemia, MS, epilepsy, and schizophrenia.
Ischemia/hypoxia
Due to perturbations of ionic gradients, glutamate uptake
through EAAT transporters is impaired during ischemia
and the rise of extracellular glutamate is believed to con-
tribute significantly to tissue damage. The possibility that
changes in the expression of EAAT transporters also occur
under ischemic conditions has been investigated for many
years.
The potential protective role of EAAT3/EAAC1 was
proposed following the cloning of the transporter [4]
and discussed in one of the first reviews concerning glu-
tamate transporters [111]. The first experimental evi-
dence of ischemia-related expression changes was pro-
vided by Martin et al. [112]; immunoblotting showed that
EAAT3/EAAC1 was reduced by 55 % in the putamen of
newborn piglets 24 h after an ischemic stress caused by
30 min of hypoxia (arterial O2 saturation, 30 %) followed
by 7 min of airway occlusion (O2 saturation, 5 %). This
decrease was possibly secondary to neuronal loss, con-
sistent with the Slc1a1 mRNA decrease demonstrated in
gerbil CA1 hippocampal neurons 24 h after a transient
ischemia [113] and the marked decrease (42–68 %) in
EAAT3/EAAC1 protein detected in the same model [114].
The latter study compared the decrease of GLT-1, which
precedes neuronal loss, with that of EAAT3/EAAC1, which
parallels cell death. Their results suggest that decreased
EAAT3/EAAC1 may have a role in GABAergic dysfunc-
tion. Decrease of EAAT3/EAAC1 expression as a conse-
quence of neuronal loss has been more recently shown by
Han et al. [115] following microsphere embolism in rats.
However, the possibility that adaptive changes in ischemic
cells may directly affect transporter expression should not
be excluded a priori [38].
A predominant role for GLT-1 in the protection from
ischemic damage was proposed by Rao et al. [116], who
showed that knock-down of this transporter, but not
of EAAT3/EAAC1, exacerbated the neuronal damage
induced by transient focal cerebral ischemia in rat brain.
Douen et al. [117] also stressed the importance of GLT-
1, using as a model rats that were preconditioned 3 days
before ischemia with cortical spreading depression (CSD)
and showed relative protection from ischemic damage.
These authors noted that extracellular brain glutamate
after ischemia was indeed lower in the preconditioned ani-
mals and that the change was associated with a decrease
of EAAT1 and EAAT2, but not EAAT3/EAAC1, expres-
sion in the plasma membrane. The authors suggested that
a lower expression of EAAT transporters contributes to
13

less glutamate efflux through the reverse operation, origi-
nally described as an alternative functional mode of EAAT
transporters under hypoxic conditions [118]. A decrease
in Slc1a1 expression under comparable conditions was
described by Montori et al. [119].
The first experimental contribution pointing to an adap-
tive and/or protective role of increased EAAT3/EAAC1
expression in ischemia came in 2000 from the Matute
laboratory [120]. These researchers compared the expres-
sion of the main EAAT transporters in the rat hippocam-
pus and cerebral cortex in both early (8 h and 1 day)
and late (28 days) phases of recovery from transient
forebrain ischemia. They found a moderate increase in
EAAT3/EAAC1 protein early after the insult, followed
by a late reduction in both CA1 pyramidal neurons and in
layer V pyramidal neurons. Moreover, the authors observed
a sustained increase in EAAT3/EAAC1 expression in oli-
godendroglial progenitor cells of subcortical white matter
[120], although, in a later study, the same group reported
that EAAT1 and EAAT2 were also up-regulated in this area
[121]. Transient changes in EAAT3/EAAC1 expression
during ischemia and the recovery phase were also reported
by Hwang [122], who described a fast decrease of trans-
porter immunoreactivity in spinal cord neurons just after
ischemia/reperfusion, followed by an increase of expres-
sion (after 3 h of reperfusion) and a further subsequent
decrease. EAAT3/EAAC1 expression was also slowly
increased, at both the mRNA and protein levels, under
“hypoxia-pure” conditions [123] in rat PC12 cells. In this
case, the maximum increase was reached after 18 h of incu-
bation at 1 % O2 and corresponded to an eightfold increase
at protein level and a four-fold increase in transport activ-
ity. However, GLT-1 was also up-regulated under the same
conditions.
These results are, at least in part, consistent with the evi-
dence obtained by Romera et al. [124] in rat cortical cul-
tures exposed to sublethal oxygen-glucose deprivation (an
in vitro model for ischemic preconditioning), and by Pra-
dillo et al. [125] in preconditioned rat brain in vivo. In both
studies, EAAT3/EAAC1 was up-regulated by increased
TNF-α signaling. However, in the same studies, TNF-
α-independent EAAT2 up-regulation was also reported.
A generalized up-regulation of EAAT transporters was
described in rat brain upon ischemic pre-conditioning by
Bigdeli et al. [126, 127].
Results from EAAC1 knock-out mice support the pro-
tective role of the transporter under ischemic conditions
[128, 129]. In particular, Won et al. demonstrated that
EAAC1−/− mice subjected to transient cerebral ischemia
exhibit much more widespread hippocampal neuronal
death than wild-type mice. These authors suggested that
impaired cysteine uptake would severely hinder intracellu-
lar glutathione synthesis, cell capability to sustain oxidative
13
M. G. Bianchi et al.
stress (expected under ischemic conditions), and main-
tenance of zinc homeostasis. N-acetyl-cysteine restored
neuronal glutathione, normalized basal zinc levels, and
attenuated ischemia-induced zinc translocation, superoxide
production, and neuron death.
Given the putative role of EAAT3/EAAC1 as a protec-
tive factor under ischemic conditions, attempts to up-regu-
late its expression have been performed as a means to limit
ischemic damage. Chen et al. [130] used intrathecal granu-
locyte colony-stimulating factor (G–CSF) to improve neu-
rological defects in the ischemic spinal cord of Wistar rats.
Using microdialysis, they found that G–CSF significantly
hampers the increase in spinal concentrations of excitatory
amino acids induced by ischemia or by exogenous intrath-
ecal administration of glutamate. These effects are associ-
ated with the increased expression of GLAST, GLT-1 and
EAAT3/EAAC1.
Multiple sclerosis
Excitotoxicity and oxidative stress have been implicated
in MS-related damage that involves not only white mat-
ter but also gray matter. However, evidence for a role of
the EAAT3/EAAC1 transporter in MS is thus far limited,
although, as detailed in the Introduction, the transporter is
also expressed in cells of oligodendrocytic lineage and, in
particular, in oligodendrocyte precursor cells [23, 24, 131].
Ohgoh et al. [132], prompted by the evidence of the
involvement of AMPA/kainate receptor in experimental
autoimmune encephalomyelitis (EAE, the animal model
of MS) [133], examined the expression of GLT-1, GLAST,
and EAAT3/EAAC1 in the spinal cord of the EAE Lewis
rat. While EAAT3/EAAC1 was dramatically increased
at both the protein and mRNA levels, GLT-1 and GLAST
were down-regulated. The AMPA/kainate receptor inhibitor
NBQX ameliorated EAE symptoms and suppressed changes
in transporter expression. No attempt was made to identify
the cell type(s) in which changes in carrier expression occur.
This issue was instead addressed by Vallejo-Illarramendi
et al. [134] who found an increase of SLC1A3 and SLC1A2
mRNA in optic nerves from MS patients, while SLC1A1
mRNA did not change. The expression increase was con-
firmed at the protein level for both EAAT1 (in oligodendro-
cytes) and EAAT2 (in astrocytes), while EAAT3/EAAC1
expression was not investigated. Increased expression of the
rodent counterparts of EAAT1 and EAAT2 (at the mRNA,
protein and function levels) were also observed in rat optic
nerves incubated with excitotoxic glutamate concentrations.
More recently, Newcombe et al. [135] studied gluta-
mate receptors, transporters, and enzymes in human MS
lesions. They found that the AMPA GluR-1 receptor subu-
nit was overexpressed in oligodendrocytes at the borders of
MS active lesions, while reactive astrocytes, macrophages,
Changes in the expression of the glutamate transporter
and neuronal structures expressed a different receptor rep-
ertoire. Unexpectedly, EAAT3/EAAC1 was expressed in
macrophages and reactive astrocytes, leading the authors to
propose that this ectopic expression may have a protective,
although not completely effective, function.
The positive effects of retinoids on EAAT3/EAAC1
expression (see above) may be important in light of the
evidence for a positive effect of retinoids in EAE mice
[136, 137]. Klemann et al. attributed the protective effect
of the synthetic retinoid Am80 to immunomodulation. On
the other hand, Huang et al. [137] attributed the protec-
tive effect of the natural compound 9-cis-retinoic acid to a
RXR-γ-dependent stimulation of oligodendrocytic differ-
entiation. Neither study, however, investigated the expres-
sion of EAAT3/EAAC1 or other glutamate transporters.
In conclusion, while some evidence suggests a role for
EAAT3/EAAC1 in the pathophysiology of MS, a definite
demonstration is still lacking.
Epilepsy
The role of EAAT3/EAAC1 dysregulation in epilepsy was
proposed in the pivotal paper in which antisense EAAT-
knock-out models were investigated for the first time
[52]. While the EAAT1 and EAAT2 knock-outs produced
severe neurotoxicity and progressive paralysis, the phe-
notype of the EAAT3/EAAC1 knock-out was milder but
associated with epilepsy. Using the same experimental
approach, it was then demonstrated that the repression of
EAAT3/EAAC1 expression was associated with decreased
tonic inhibition and to 50 % loss of hippocampal GABA
levels, attributable to the impairment of GABA synthesis
from extracellular glutamate [65].
These early findings spurred many investigations with
experimental models of epilepsy. Compared to controls,
Slc1a1 mRNA was markedly increased in dentate granule
cells from rats with pilocarpine-induced epilepsy and in
human dentate granule cells from patients with temporal
lobe epilepsy (TLE) [138]. In cortical dysplasia, the trans-
porter mRNA was elevated in human dysplastic neurons
compared with non-dysplastic neurons. These changes
were confirmed at the protein level and were interpreted as
an attempt to compensate for the higher-than-normal extra-
cellular glutamate levels caused by recurrent seizures [138].
Pilocarpine-induced status epilepticus has been associated
with an increase in EAAT3/EAAC1 protein in rat hip-
pocampus and with a ~15-fold increase in Slc1a1 mRNA in
rat synaptoneurosomes [139], although the authors attrib-
uted the change more to the targeting of the messenger to
dendrites than to an effect on transcription [140].
Doi et al. [141] examined the induction of epilepsy
(kindling) by pentylenetetrazol (PTZ) in rats. They found
that the expression of hippocampal glutamate transporters
(not only EAAT3/EAAC1 but also GLAST and GLT-1)
increased within 24 h by kindling but returned to basal
levels 30 days after the last seizure. These findings led
the authors to suggest that glutamate transporters may
contribute to the occurrence of seizures. Interestingly,
easily-kindled rats had levels of EAAT3/EAAC1 and
GAT-1 (the GABA transporter) that were 30 % lower com-
pared to epilepsy-resistant animals, again suggesting that
EAAT3/EAAC1 level is negatively associated with the con-
vulsive threshold [141].
Voutsinos-Porche et al. reported the temporal depend-
ence of epilepsy-associated changes in transporter expres-
sion, demonstrating that EAAT3/EAAC1 increased in sev-
eral portions of the hippocampus during the acute period of
status epilepticus, but returned to control levels in the CA1,
2, and 3 layers during the latent period. The authors con-
cluded that “it is not clear to what extent the overexpression
of EAAT3/EAAC1 contributes to epileptogenesis and in
which area it may represent a preventive or compensatory
or response to injury” [142].
Using the model of kainate-induced convulsions, Sim-
antov et al. [143] reached apparently divergent conclusions.
Kainate acutely lowered EAAT3/EAAC1 in the stratum
lacunosum moleculare, and the decrease in protein level was
associated with a decrease in mRNA. Opposite effects were
reported for GLT-1, leading the authors to conclude that dif-
ferential regulation of neuronal and glial EAAT may contrib-
ute to kainate-induced seizures. In another model of experi-
mental epilepsy due to prenatal exposure to the teratogen
methylazoxymethanol, heterotopic hippocampal neurons
exhibited striking reductions in EAAT3/EAAC1, as well as in
GluR1 NMDA receptor subunit expression [144]. In contrast,
a significant increase in the carrier expression was detected in
hippocampal and motor cortex area neurons of rats with chest
compression-induced audiogenic epilepsy [145].
Data from human tissues are contradictory. Proper
et al. [146] reported an increase in EAAT3/EAAC1 in
individual neurons of the hippocampus of TLE patients,
although the functional consequences of the reported
changes are unclear. Increased EAAT3/EAAC1 expres-
sion was also reported by Mathern et al. [147], but only in
epileptic patients with hippocampal sclerosis. On the other
hand, Rakhade and Loweb [148] measured the differential
expression of EAAT1–4 at the mRNA and protein levels in
electrically mapped human neocortical tissues and found
significant reductions of EAAT3/EAAC1 and EAAT4)
at both the mRNA and protein level, not associated with
changes in the relative neuronal density. The authors con-
cluded that “regional reductions in EAAT expression at
human neocortical epileptic foci could produce increased
local glutamate levels that in turn may contribute to both
hyperexcitability and the spontaneous generation of epilep-
tic discharges that characterize human epileptic foci” [148].
13

As far as genetic forms of epilepsy are concerned, Dutuit
et al. [149] described a 32 % decrease in EAAT3/EAAC1
expression in the thalamus of young genetic absence epi-
lepsy rats from Strasbourg (GAERS) compared to con-
trols. However, the expression of GLT-1 and GLAST also
decreased, and the changes were not observed in adult
animals.
Interestingly, in human gangliogliomas, which are
neuronal-glial tumors strongly associated with epilepsy,
SLC1A1 is among the genes that are down-regulated com-
pared to normal tissue [150]. This alteration has been
attributed to a true transcriptional change rather than to a
compensatory response to high extracellular glutamate due
to repeated seizures. In contrast, the high expression of
SLC1A1 mRNA detected in the lesions of patients affected
by tuberous sclerosis, another condition exhibiting high sei-
zure incidence, has been considered compensatory [151].
Schizophrenia
The possibility that glutamatergic transmission is altered in
schizophrenic patients has been debated for several years.
Changes in the expression of EAAT1 and EAAT2, but
not EAAT3/EAAC1, have been detected in the thalamus
[152] or the superior temporal gyrus and the hippocam-
pus [153]. While these studies do not support a role for
EAAT3/EAAC1 in schizophrenia, the findings suggest that,
in addition to glutamate receptors, alterations in glutamate
Fig. 1  Sites of regulation of EAAT3/EAAC1 expression on the
plasma membrane. The sketch depicts the three documented sites of
regulation of EAAT3/EAAC1 expression: changes in SLC1A1 tran-
scription, modulation of carrier interaction with binding proteins and
13
M. G. Bianchi et al.
transport may also contribute to the glutamatergic dysfunc-
tion implicated in schizophrenia.
Other reports present evidence for a role of
EAAT3/EAAC1 in schizophrenia. Increased carrier tran-
scripts and proteins were reported in schizophrenic subjects
(dorsolateral prefrontal and anterior cingulated cortex) by
Bauer et al. [154]; these findings were, more recently, con-
firmed by Rao et al. [155] in the frontal cortex at both the
protein and mRNA levels. Conversely, Lauriat et al. [156]
did not observe differences in EAAT3/EAAC1 expression
in either the dorsolateral prefrontal or the primary visual
cortex. However, the authors also highlighted the pos-
sibility that the results were influenced by antipsychotic
treatment that is often prolonged for many years in these
patients [156].
On the contrary, decreased SLC1A1 transcript expres-
sion in the striatum was observed in schizophrenia (and in
bipolar disorder) by other authors [157] and confirmed in
schizophrenic patients in a later study [158].
Conclusions and perspectives
The regulation of EAAT3/EAAC1 expression at the gene
level is far less characterized than mechanisms acting on
transporter trafficking. Nevertheless, accumulating data
yield an increasingly complex picture (Fig. 1), indicating
that at least three levels of control modulate the expression
modification of transporter trafficking to and from the plasma mem-
brane. For changes in SLC1A1 transcription, transcription factors,
chromatin-modifying enzymes, and extracellular stimuli known to be
involved in expression changes are detailed
Changes in the expression of the glutamate transporter

Table 1  Selected conditions and stimuli associated with changes in the expression of EAAT3/EAAC1
Condition/stimuli SLC1A1/Slc1a1 EAAT3/ Models References
mRNA EAAC1

Alzheimer dementia ND ↑ Mouse (Abeta PP23) hippocampus [108]

ND ↓ Mouse (3×Tg-Alzheimer’s disease) [109]
hippocampus
Dicarboxylic aminoaciduria ND ↓ Canine kidney cell line [12]
Epilepsy (kainate-induced convulsions) ↓ ↓ Rat hippocampus [143]
Epilepsy (methylazoxymethanol) ↓ ↓ Rat hippocampal neurons [144]
Epilepsy (pilocarpine-induced, temporal lobe ↑ ↑ Human hippocampus [138]
epilepsy, TLE) ↑ ↑ Rat hippocampal neurons [139]
↑ ↑ Rat hippocampal granule cells [140]
↓ ↓ Human neocortical tissues [148]
Exercise ↑ ND Rat hippocampus in vivo [99]
Experimental autoimmune encephalomyelitis ↑ ↑ Rat spinal cord [132]
(EAE)
G–CSF ND ↑ Rat spinal cord [130]
HDAC inhibitors ↑ ↑ Human oligodendroglioma Hs683 cells [79]
(valproic acid, trichostatin A)
Hypertonic stress ↑ ↑ Bovine renal epithelial NBL-1 cells [85, 88]
Hypoxia (pure) ↑ ↑ Rat pheochromocytoma PC-12 cells [123]
Ischemia/hypoxia ND ↓ Piglet striatum [112]
↓ ↓ Gerbil hippocampus [113]
↓ ↓ Gerbil hippocampus [114]
↓ ND Rat hippocampus and cerebral cortex [119]
ND ↓ Rat neurons and oligodendrocytes [120]
ND ↑ Rabbit spinal cord [122]
Ischemic preconditioning ↑ ↑ Rat cortical neurons in culture [124]
(oxygen-glucose deprivation) ↑ ↑ Rat brain in vivo [125]
NrF2 ↑ ↑ Rat brain neurons in situ and in vitro [95]
Retinoids (all-trans retinoic acid and Am80, a ↑ ↑ Rat glioma C6 cells [82, 83]
synthetic retinoid)
RFX1 ND ↑ Rat glioma C6 cells; rat brain neurons in situ [91]
Schizophrenia ↑ ↑ Human cortex [154]
↑ ↑ Human frontal cortex [155]
↓ ND Human striatum [157]
Tunicamycin (ER stress?) ↑ ↑ Bovine renal epithelial NBL-1 cells [88]

ND not determined

of the transporter on the plasma membrane: transcriptional
changes in SLC1A1 expression (Table 1), changes in protein
interaction, and trafficking modulation. Overall, this infor-
mation suggests that EAAT3/EAAC1 can be finely regu-
lated at the gene level; however, detailed information is not
yet available on regulations acting at post-transcriptional or
translational sites. With respect to the well-known exam-
ples of fast trafficking modulation, transcriptional regula-
tions are clearly slower but may be more relevant to explain
the somewhat contradictory changes in EAAT3/EAAC1
expression described in situations of pathophysiological
interest and associated with chronic alterations in nerv-
ous functions. Improved knowledge of these mechanisms
is necessary to clarify the role of EAAT3/EAAC1 in these
conditions and, more importantly, to envisage novel thera-
peutic approaches.
Acknowledgments  Research in the authors’ laboratory has been
funded by FISM (Fondazione Italiana Sclerosi Multipla onlus), grant
no. 2010/R/9 to OB.
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