Glutamate is implicated in the neuropathology of both major depressive disorder and bipolar disorder. Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the mammalian brain, removing glutamate from the synaptic cleft and transporting it into glia for recycling. It is thereby the principal regulator of extracellular glutamate levels and prevents neuronal excitotoxicity. EAAT2 is a promising target for elucidating the mechanisms by which the glutamate-glutamine cycle interacts with neuronal systems in mood disorders. Forty EAAT2 studies (published January 1992–January 2018) were identified via a systematic literature search. The studies demonstrated that chronic stress/steroids were most commonly associated with decreased EAAT2. In rodents, EAAT2 inhibition worsened depressive behaviors. Human EAAT2 expression usually decreased in depression, with some regional brain differences. Fewer data have been collected regarding the roles and regulation of EAAT2 in bipolar disorder. Future directions for research include correlating EAAT2 and glutamate levelsin vivo, elucidating genetic variability and epigenetic regulation, clarifying intracellular protein and pharmacologic interactions, and examining EAAT2 in different bipolar mood states. As part of a macromolecular complex within glia, EAAT2 may contribute significantly to intracellular signaling, energy regulation, and cellular homeostasis. An enhanced understanding of this system is needed.

Mood disorders cause a significant burden of disease worldwide. Globally, depression has a prevalence of 4.4% [1], affecting approximately 322 million people, with significant loss of quality-adjusted life years and productivity, and increased risk of suicide. Bipolar disorder (BD) has an estimated prevalence of up to 4.4% in the US population [2] and is associated with elevated suicide risk and significant morbidity. Depression and BD are clinically heterogeneous mood disorders which, in mania or severe depression, can present with psychotic symptoms. As the major excitatory neurotransmitter of the mammalian brain, glutamate has been associated with both mood and psychotic disorders [3, 4]. Released by presynaptic neurons, glutamate is transported into surrounding glial cells and recycled back to glutamine. Glutamine is the precursor molecule to both glutamate and γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. This glutamate-glutamine cycle helps regulate neuronal excitability [5].

The main glutamate transporter in the mammalian brain is the excitatory amino acid transporter 2 (EAAT2), also called glutamate transporter 1 (Glt-1) in rodent literature, or solute carrier family 1 member 2 (SLC1A2). It is encoded by the SLC1A2gene and inhibited by dihydrokainate (DHK) [6]. EAAT2 plays a crucial role in preventing extracellular glutamate concentrations from reaching neurotoxic levels [7] and in recycling glutamate at synapses by transporting glutamate into astrocytes for conversion to glutamine (Fig. 1). This figure also illustrates an overview of the multiple dynamic interactions between glutamate receptors and transporter subtypes within the glutamate cycle. There are five mammalian EAAT isoforms (EAAT1–5) of the solute carrier 1 (SLC1) glutamate transporter family [8]. EAAT isoforms have different tissue localizations, amino acid sequences, and pharmacological profiles. Only EAAT1 (also known as glutamate-aspartate transporter, GLAST) and EAAT2 are expressed in astrocytes. EAAT2 is additionally expressed on axon terminals [9]. EAAT3 is fairly ubiquitously expressed in neuronal tissue, with high intracellular and postsynaptic terminal concentrations, possibly for rapid buffering of local glutamate changes [10].

Fig. 1.

Representation of roles of EAAT2 in both preventing extracellular glutamate concentrations from reaching neurotoxic levels and in recycling glutamate at synapses, by transporting glutamate into astrocytes for conversion to glutamine. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoazole-propionic acid receptor; AQP4, aquaporin 4; EAAT, excitatory amino acid transporter; Gln, glutamine; Glu, glutamate; KAR, kainate receptor; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartic acid receptor; SAT, system A transporter; SN1, system N transporter.

Fig. 1.

Representation of roles of EAAT2 in both preventing extracellular glutamate concentrations from reaching neurotoxic levels and in recycling glutamate at synapses, by transporting glutamate into astrocytes for conversion to glutamine. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoazole-propionic acid receptor; AQP4, aquaporin 4; EAAT, excitatory amino acid transporter; Gln, glutamine; Glu, glutamate; KAR, kainate receptor; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartic acid receptor; SAT, system A transporter; SN1, system N transporter.

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Glutamate transporters share 25–30% homology [11], and the structure of EAAT2 is partially extrapolated from homologs. EAAT2 is a bowl-shaped homotrimer with a large central water-filled cavity extending into the cell membrane [12]. Each monomer contains glutamate-binding sites and transport pathways and can probably bind and transport glutamate independently of the other monomers [13]. Each monomer core contains substrate- and ion-binding sites and is comprised of two hairpin loops (HP1, HP2) which may comprise the internal and external gates of the transporter and multiple transmembrane (TM1–8) segments. Glutamate and kainate induce distinct conformational changes in the external gate of EAAT2 [14]. EAAT2 is believed to co-transport glutamate with three sodium ions and one hydrogen ion down concentration gradients into the cell, with sequential counter-transport of one potassium ion; each monomer also contains a chloride channel, possibly a feedback system reducing glutamate release [15]. EAAT2 is part of a macromolecular complex that includes aquaporin-4 (AQP4) [16], a water channel that plays a key role in ion and fluid homeostasis within the brain [17]. This complex further includes other membrane proteins, mitochondria, and glycolytic enzymes, suggesting complex regulatory and homeostatic functions [18]. AQP4 may buffer astrocytic water volume affected by EAAT2 activation [19]. AQP4 is of clinical interest in a wide variety of neurological conditions, including neuromyelitis optica, epilepsy, Alzheimer’s dementia, traumatic brain injury, and Parkinson’s disease.

EAAT2/Glt-1 displays transcript variants [20], and Glt-1a and Glt-1b are the most commonly described. The two splice variants have different cellular and subcellular expression profiles [21]. EAAT2 is differentially expressed across anatomical regions in different psychiatric conditions. For example, rodent depression models demonstrate increased hippocampal Glt-1a mRNA/protein, but schizophrenic humans have decreased parahippocampal and dorsolateral prefrontal cortex EAAT2 [7]. Pharmacologic studies also find associations between EAAT2 and neuropsychiatric disorders: riluzole, ceftriaxone, and steroids are medications that alter EAAT2 expression and may have antidepressant effects in rodents [22, 23]. Riluzole is a sodium channel blocker that upregulates EAAT2 protein levels, reduces synaptic glutamate release, and inhibits ionotropic glutamate receptors [22]. Ceftriaxone is a β-lactam antibiotic which upregulates EAAT2 levels and glial glutamate uptake, and has been investigated for the prevention of alcohol withdrawal [24]. Glucocorticoids cause immediate hippocampal Glt-1 mRNA/protein increases in rodent stress models [25, 26], followed by gradual decreases after chronic exposure [22].

The role of EAAT2 in selected disease processes has been summarized previously [8]. This review summarizes the current state of knowledge of the roles of EAAT2 in unipolar and bipolar mood disorders. For precision, we refer to Glt-1 in rodent studies, and EAAT2 in human studies.

We conducted a comprehensive literature search of PubMed, PsycInfo, and Web of Science from 1 January 1992 [27] through 15 January 2018. Database-specific truncations ensured that searches included singulars/plurals and alternate suffixes or spellings. Boolean search string was: Title, Abstract, Keywords/MeSH terms (EAAT2 OR SLC1A2 OR Glt-1 OR “excitatory amino acid transporter” OR “solute carrier family 1 member 2” OR “glutamate transporter 1”) AND Title, Abstract, Keywords/MeSH terms: (bipolar OR depress* OR unipolar). Articles were collated in EndNote X8 (Clarivate Analytics, Philadelphia, PA, USA). Duplicates were removed by the software via author, year, title, and journal comparison, and any remaining duplicates were removed manually by first author. Each abstract was reviewed independently by first and final authors. Sixty-seven articles were selected for full text review (Fig. 2).

Fig. 2.

Flow diagram of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria search strategy for systematic literature review.

Fig. 2.

Flow diagram of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria search strategy for systematic literature review.

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Literature was eligible for inclusion: (1) if it discussed the roles, functions, interactions, or regulation of EAAT2 in human patients with BD or unipolar depression, or mammalian models (behavioral, genetic, or pharmacological) of BD or unipolar depression, or models of molecular interactions in BD or unipolar depression; (2) if the full text was available in English; and (3) if it was published in print or electronically between January 1992 and January 2018. Exclusion criteria were: (1) studies inducing mood symptoms through brain tissue damage (ischemia, surgical resection, etc.); (2) genetic models of non-mood disorder diseases; and (3) in silico models of molecular interactions. Forty articles met all the inclusion criteria. Twenty-six described animal models of depressive or bipolar symptoms [17, 22, 25, 26, 28‒47]. Sixteen described human studies of major depressive disorder (MDD) and/or BD [48‒63]. The papers are summarized in Tables 1 and 2. Each experimental paper was reviewed for design, sample size, description and duration of experiment, types of controls, how results were obtained and analyzed, and experimental findings. Data were extracted independently and in duplicate. Studies were appraised for quality using a modification of a published review process [64]; all papers met a quality score of moderate or high.

Table 1.

Summaries of animal studies included in the systematic analysis

 Summaries of animal studies included in the systematic analysis
 Summaries of animal studies included in the systematic analysis
Table 2.

Summaries of human studies included in the systematic analysis

 Summaries of human studies included in the systematic analysis
 Summaries of human studies included in the systematic analysis

Glt-1 Expression in Animal Models of Mood Disorders

Animal studies frequently model depression via uncontrollable stress (e.g., chronic restraint, territorial intrusions, electric shocks, social isolation, social defeat) to induce learned helplessness and behavioral evidence of despair and anhedonia [29, 65]. Acute stress increases synaptic glutamate release and glutamate clearance in the PFC, while chronic stress decreases glutamate receptors, reduces glutamate recycling, and alters glutamate regulation [66]. Since stress responses are mediated by the HPA axis, corticosteroid administration is also used to model depression.

Rodent Stress Models of Depression

Studies of Glt-1 in rodent mood models have produced conflicting results. Earlier studies reported that stress upregulated hippocampal Glt-1 expression [25, 26, 37], possibly as a neuroprotective response to stress-induced synaptic glutamate increases [39]. Later studies demonstrated that chronic stress downregulated Glt-1 in both rats [29, 32, 35, 36] and mice [37, 42].

In rats, chronic unpredictable stress decreased hippocampal Glt-1 protein without changing EAAT1/GLAST [45]. Chronic stress also significantly decreased hippocampal EAAT2/Glt-1 and EAAT3 protein levels (encoded by SLC1A2 and SLC1A1, respectively), in addition to associated depressive behaviors [46]. Stress may decrease Glt-1 partially via phosphodiesterases, since the phosphodiesterase 4D inhibitor (GEBR-7b) prevented stress-induced hippocampal Glt-1 protein decreases in rats [36].

Sex-specific effects in Glt-1 expression have also been reported. In stressed rats, compared to controls, females demonstrated reduced Glt-1 protein in the PFC, while males showed reduced Glt-1 in the striatum [40]. Prenatal stress administered to pregnant rats significantly reduced hippocampal, frontal cortex, and striatum Glt-1 levels in male rat offspring and was associated with increased depressive behaviors [43, 44]. Female offspring were not assessed. Prenatal stress reduces glial cells in animals and humans, and sex differences in hippocampal glial numbers have been reported, with female offspring in a prenatal stress model demonstrating significant glial reduction, depressed behaviors, and cognitive deficits compared to male offspring [67]. Since Glt-1 is preferentially expressed in glia, it is important to consider whether Glt-1 decreases are due to changes in transcription/translation, or to a loss of glial cells expressing Glt-1. Correlating Glt-1 levels and glial numbers across species and between brain regions would help interpret these results.

Strain-specific responses were seen both within mice [37] and rats [41]. Chronic stress increased hippocampal Glt-1 levels in DBA/2J mice (a strain bred for extreme intolerance to alcohol/morphine and susceptibility to seizures) but decreased Glt-1 levels in seizure-resistant C57BL/6J mice and other strains [37]. DBA/2J astrocytes have previously demonstrated much higher rates of GABA synthesis than C57BL/6J and higher glutamate-to-GABA ratios [68]. This suggests the distinct Glt-1 stress may be related to an underlying difference in the glutamate/glutamine/GABA system, though it remains unclear whether this involves altered gene transcription, protein expression, transport activity, or GABA synthesis. Different Glt-1 responses to stress have also been seen in rats [41]. Rats bred for helpless behavioral responses to chronic stress were examined within strain, to see whether they displayed helplessness or stress resistance. Their behavior was also compared to that of control rats [47]. The stress-susceptible/behaviorally resilient strain and the control rats retained higher levels of Glt-1, while the stress-susceptible/behaviorally helpless strain had decreased Glt-1 mRNA/protein. Reduced astroglial glutamate uptake and increased glutamate levels were seen in these genetically and behaviorally helpless rats.

Pharmacological Models of Depression and Glt-1 Modulation

Chronic corticosteroid administration induced depressive behaviors in rodents [17, 22, 39]. In rats, corticosterone treatment increased hippocampal Glt-1 [39]. In mice, steroids reduced hippocampal BDNF and GLAST, glial neurotrophic factor, and neurogenesis in mice, but did not significantly change Glt-1 [17, 22]. However, in AQP4 knockout mice, 20 mg/kg corticosterone daily for 21 days significantly downregulated Glt-1 protein [17]. Differences in Glt-1 expression within these mouse strains may reflect an effect of AQP4 function. AQP4 knockouts have a reduction in astrocyte number and greater astrocytic vulnerability to steroid-induced injury [17]; their loss could account for the Glt-1 protein level decrease.

In mouse models of steroid-induced depression, riluzole reversed steroid-induced hippocampal Glt-1 suppression and prevented despair behaviors [22], while increasing Glt-1 hippocampal protein in controls. Exercise also reversed social isolation-induced hippocampal Glt-1 protein decrease in rats [32]. A complex study of the molecular and behavioral effects of alcohol withdrawal in rats found that depressive and anxious behaviors could be reversed by ceftriaxone (which upregulates EAAT2 [24]), but they reappeared after DHK treatment [34]. Alcohol withdrawal was associated with significant Glt-1 protein reduction in lateral habenula, which was normalized by ceftriaxone.

Four papers examined the behavioral and molecular consequences of Glt-1 inhibition in rodents [28, 30, 31, 33]. DHK is a specific Glt-1 inhibitor [6]. In Sprague-Dawley rats, DHK infusion to the lateral ventricles [28] and amygdala [33] resulted in anhedonic/dysphoric behaviors as measured by intracranial self-stimulation. DHK infusion increased c-Fos (a proto-oncogene expressed by neurons after depolarization, and a proxy for neuronal activity) in reward and mood brain regions, including the nucleus accumbens, amygdala, and infralimbic cortex [28]. Mice with acute Glt-1 inhibition (via DHK) and chronic Glt-1 inhibition (floxed Glt-1knockout) displayed depressive behaviors, reduced resilience to chronic stress, and sleep changes, with increased excitability of their lateral habenula neurons, which are typically activated by unpleasant stimuli [30]. In Wistar rats, DHK infusion to the infralimbic cortex prevented depression-like behavioral responses in stressful scenarios, though DHK had no effect when administered to the prelimbic cortex [31]. The infralimbic result differs from previously reported DHK-induced depressive behaviors. It is unclear whether the difference is related to strain differences between Sprague-Dawley and Wistar rats, or Glt-1 function in the infralimbic cortex. Although DHK is a specific inhibitor of Glt-1 and therefore acts on the glutamate system, the same study found that its antidepressant effect was prevented by serotonin depletion and AMPA glutamate receptor antagonism, while an antidepressant response was seen with the AMPA agonist (s-AMPA). These results probably reflect the complex interplay of multiple neurotransmitter systems in depression and suggest that a Glt-1 inhibitor cannot reverse despair behavior in a serotonin-depleted or glutamatergically inhibited brain.

Several papers explored the pharmacological modulation of Glt-1 expression in depression models [22, 25, 26, 29‒31, 35, 37, 38, 44‒46], including antidepressant agents (fluoxetine, citalopram, escitalopram, ketamine, nortriptyline, and tianeptine) and their effect on Glt-1. In rats, fluoxetine reversed stress-induced depressive behaviors and hippocampal Glt-1 decreases [29]. In mice, fluoxetine improved depressive behaviors even in the presence of DHK-induced Glt-1 inhibition [30] and had no effect on hippocampal Glt-1 protein levels [38]. In summary, fluoxetine improved depression-like behaviors in mice and rats, but only normalized hippocampal Glt-1 levels in rats without altering reduced hippocampal Glt-1 levels in mice. Various explanations for differential Glt-1 expression in response to fluoxetine include dose response and acuity (rats received fluoxetine 10 mg daily for 4 weeks [29], while mice received fluoxetine 20 mg/kg as a single dose [30] or daily for 7 days [38]), or species response differences. In rats, stress increased hippocampal Glt-1a and Glt-1b, and the tricyclic antidepressant (tianeptine) prevented Glt-1a increases, but not Glt-1b [25]. There were also marked differences in the effect of antidepressants across mouse strains [37]. In three strains (C57BL/6J, 129S1/SvemJ, FVB/NJ) chronic stress increased Glt-1 mRNA, while the antidepressants escitalopram and nortriptyline decreased Glt-1, but in the fourth strain (DBA/2J) the opposite was demonstrated: stress decreased Glt-1 mRNA, while antidepressants increased it.

Ketamine is used off-label for rapid treatment of depression [69]. In rats, ketamine significantly reversed stress-induced decreases of hippocampal Glt-1 mRNA, decreased stress-induced hippocampal glutamate increases, and reversed depression-like behaviors (spontaneous locomotion, sucrose preference) [35, 46]. The effect of ketamine on Glt-1 may be modulated through BDNF-TrkB signaling, since the ketamine-induced Glt-1 changes were prevented when rats were pretreated with a TrkB receptor inhibitor [35]. Lithium is a mood stabilizer used in BD and (without Food and Drug Administration indication) in depression treatment and prophylaxis. In rats with stress-induced increased hippocampal Glt-1 mRNA, lithium prevented both this and loss of dendrite length [26].

Electroconvulsive shock (ECS) is an animal model of electroconvulsive therapy (ECT) which is a clinical treatment for depression in humans. Unlike ECT, however, ECS induces seizures in typically awake animals and therefore is itself a potential stressor. In chronically stressed rats, ECS further downregulated Glt-1, increased hippocampal glutamate, and worsened behavioral markers of depression [45]. The anesthetic agent propofol significantly normalized stress-induced and ECS-induced Glt-1 downregulation, glutamate concentration, and behavior [45].

Icariin is a flavonoid extracted from Horny Goat Weed and used extensively in Chinese traditional medicine, with antidepressant and neuroprotective effects in rodents. In prenatally stressed rats, icariin administered to male offspring reduced stress-elevated group I metabotropic glutamate receptors (mGluR1/5) mRNA and protein levels, and increased stress-reduced EAAT2 mRNA and protein levels. Zinc or fluoxetine decreased stress-induced depressive behaviors, but neither altered hippocampal Glt-1 levels [38].

Human Studies

Genetic Findings

Although several studies have analyzed genetic associations of SLC1A2with mood disorders, no SLC1A2 single nucleotide polymorphism (SNP) has a confirmed diagnostic association with MDD or BD. In the currently available GWAS data from the Psychiatric Genomics Consortium (PGC) no SNP within a 20-kb window of SLC1A2reaches GWAS significance for MDD [70] or BD [71], or schizophrenia [72] (no association having a p value lower than 5 × 10–4). It is possible that rare variants may be detected in future sequencing studies, and for now this remains speculative. However, positive genetic correlations have been reported for subphenotypes of mood disorders. For example, minor alleles within SLC1A2 have been associated with the rapid cycling subtype of BD [73]. Additionally, SLC1A3 and SLC1A2 polymorphisms have been studied in mood and psychotic disorders, and found to be associated with differences in cognition, memory, executive function, suicide completion, and medication responses [74, 75]. The effects of 28 SNPs in 18 candidate genes were studied in a mixed population of 159 psychiatric patients including 85 MDD and 9 BD patients [58]. rs4755404 (an SNP in an intronic region of SLC1A2) was significantly associated with suicide attempts. Testing for associations with other clinical variables such as diagnosis, an association with schizophrenia and other psychotic disorders was found in a dominant model, but no effect was seen for MDD or BD, though associations with diagnoses was not the primary focus of the study. A functional SNP, rs4354668 (SLC1A2–181 A>C), affecting protein expression and plasma glutamate levels [76], was studied for its effect on history of illness in BD (n = 110) [51]. This study found that T/T homozygotes had a significantly lower mood episode frequency, while G/G homozygotes experienced higher mood episode recurrence (depressive, manic, mixed-state) and an increased mania-to-depression ratio. Furthermore, a multivariate analysis revealed an interaction between the genotype and lithium treatment with the effect of the genotype on episode recurrence rate only being present in lithium-untreated patients. The G allele of SNP rs4354668 (within the promoter region of SLC1A2) is associated with decreased EAAT2 activity and increased plasma ­glutamate concentrations [60]. The minor allele T of rs43534668 was associated with reduced hippocampal gray matter volume, but only in patients with low numbers of adverse childhood experiences (ACEs) [61]. Patients with high ACEs displayed an overall reduction in gray matter volume compared to patients with low ACEs that was not further reduced in subjects with the T allele. Complete histories of psychopharmacological treatments were limited, but lifetime lithium exposure did not alter allelic associations. An association between brain volume and number of mood episodes was not reported. The rs43534668 G allele has been associated with worse cognition (executive function and working memory) in schizophrenia, but this effect was not observed in BD [60].

The largest genetic study of SLC1A2in BD included 1,099 BD patients and 1,095 controls [52]. Its primary analysis included nonsynonymous variants, intron/exon junction variants, and SNPs in the putative regulatory region, whose minor allele frequency was unknown or <0.01. Two recurrent missense variants (rs145827578:G>A, rs199599866:G>A) and one recurrent 5′-UTR variant (ss825678885:G>T) were found in BD cases only (3, 1, and 2, respectively) and not controls; none of the analyzed SNPs reached statistical significance alone. Taking advantage of the large sample size, the authors also tried to replicate previous studies but found no association of rs4755404 with attempted suicide [58] and no association of rs4354668 with lithium efficacy, defined as a reduction in mood episode number [51].

Molecular Differences by Brain Region

Prefrontal Cortex. The prefrontal cortex (PFC) is an association cortex crucial to human cognition, organizing input from diverse sensory modalities, maintaining attention, working memory, and coordination of goal-directed behaviors. It comprises several Brodmann areas (BA) anterior to primary motor and premotor cortices, responsible for executive functioning (BA9/10/46), language processing (BA44/45), and emotional processing and sociability (BA47/10/11/13) [77]. The PFC has been studied in many psychiatric disorders, with differences found in conditions including autism, schizophrenia, MDD, and BD. Six articles studied EAAT2 expression for this brain region in MDD and BD [49, 50, 57, 59, 62, 63]. Microarray analysis of gene expression in the dorsolateral PFC (DLPFC: BA9/46) in MDD, BD, and controls found SLC1A2downregulated in MDD (fold change: 0.71, p < 0.05) but not in BD [50]. Attempted verification by in situ hybridization (ISH) observed a nonsignificant downward trend. A partial corroboration [59] reported that SLC1A2expression was significantly reduced in DLPFC white matter (BA46) of MDD compared to controls and found a trend for reduced expression of SLC1A2 in superficial and deep gray matter. However, the differences were very small and the p values were not corrected for multiple testing. Furthermore, the authors report a correlation between GAD1 (glutamate decarboxylase 1) and SLC1A2 gene expression in the deep gray matter of BA46 in MDD but not in controls. No significant results were reported for BD. Adding to gene expression data, EAAT2 protein expression in the left orbitofrontal cortex (BA47) of patients with MDD, MDD + alcoholism (MAD), alcoholism, and controls was examined [57]. Immunohistochemistry found significantly reduced EAAT2 protein levels in MDD and MAD but not in alcoholism alone, when compared with controls. The same trend was observed in Western blot, but the results were not statistically significant. Another study based on microarray analysis of gene expression in DLPFC in BD reported elevated EAAT2 levels after correcting for pH and age. However, this increase could not be validated by qPCR, with the authors speculating this was due to targeting the wrong region of the gene [62]. In contrast to these findings are reports of no differences in gene expression in homogenized PFC (BA10) between matched MDD and controls [49]. Grouping patients by age and suicide status found young MDD patients without suicide had elevated DLPFC (BA9) EAAT2 levels on qPCR when compared to controls and young MDD suicides [63]. No difference in gene transcription was found between violent and nonviolent suicide methods and no differences were reported between MDD and controls, or between MDD and controls in older patients, even when grouped according to suicidal ideation.

Anterior Cingulate Cortex. The anterior cingulate cortex (ACC) is part of the limbic system and surrounds the anterior part of the corpus callosum, comprising BA24, 32, and 33. It appears to play important roles in both autonomic and higher-level cognitive functions, including pain processing, performance monitoring, value encoding, decision making, emotions, learning, and motivation [78]. The ACC has been heavily studied in psychiatric disorders and has been associated with MDD, schizophrenia, and ADHD. One study described a trend in ACC similar to DLPFC: significant downregulation of SLC1A2 in microarray with a downward trend strongest in layer 2 [50]. In a direct comparison between the two brain regions between all patients and controls, ACC had higher SLC1A2expressionthan DLPFC. A separate study found no differences in ACC SLC1A2levels in MDD compared to controls, nor in any of the other comparisons (young suicidal vs. nonsuicidal vs. controls; older patients vs. controls; older patients with suicidal ideation vs. controls) [63]. However, a weak correlation (p = 0.036) between levels of SLC1A2and TrkB.T1 (the truncated receptor of BDNF) was reported in MDD patients regardless of suicidal ideation.

Locus coeruleus. The locus coeruleus (LC) is the primary site of central nervous system norepinephrine synthesis and is involved in autonomic responses (arousal, sleep/wake cycles, stress response) and higher cognition (attention, memory, perception, motivation) [79]. Differential expression in the midrostral LC of genes involved in glutamate signaling was studied in healthy controls and MDD [48]. SLC1A2was decreasedin microarray and qPCR, but not ISH, with no differences between BD and controls. A separate study of glutamatergic and astrocytic markers in postmortem homogenized pontine LC and microdissected astrocytes/oligodendrocytes found no differences in LC SLC1A2expression between MDD and controls [49]. However, there was a significant reduction of SLC1A2 in astrocytes (p < 0.001) but not oligodendrocytes in MDD compared to controls.

Striatum. The striatum is part of the subcortical basal ganglia and plays an important role in motor and reward systems, including reward cognition, reinforcement, and motivation. It receives glutamatergic and dopaminergic inputs. One study reported no difference in EAAT2 mRNA levels measured by ISH in the ventral striatum, caudate, or putamen between MDD and BD diagnoses [54]. However, EAAT2 mRNA levels were significantly lower in the ventral striatum than in the caudate nucleus and putamen across all diagnoses and controls.

Hippocampus. This brain region is primarily involved in memory formation. A study of microdissected hippocampus in MDD, BD, and healthy controls found a significant downregulation of EAAT2 in MDD but not BD patients by microarray and ISH [55]. These results were confirmed when measuring samples from the same cohort by qPCR (p = 0.002) [56].

EAAT2 may play a role in the etiology and phenotype of mood disorders but the data are still contradictory. Possible mechanisms include preventing glutamate excitotoxicity, regulation of glutamate release, modulating glutamatergic receptor activation, and (as part of a macromolecular complex) intracellular water/ion homeostasis and energy metabolism. Gross neuronal injury results in a massive release of glutamate [80, 81], activating glutamate receptors and causing an excitotoxic cascade [82]. Excitotoxicity causes injury and death of all three components of the neurovascular unit (neuron, glia, vascular cells) [83], further reducing EAAT2 levels while releasing additional glutamate. Glutamate neurotoxicity as a mechanism in psychiatric disorders remains hypothetical [84] but is already being explored in vivo via magnetic resonance spectroscopy (MRS) [85]. MRS combines glutamate + glutamine (the nonexcitotoxic precursor) as a Glx measurement, and studies have found that MDD is typically associated with decreased Glx, while BD is associated with increased Glx. Such data could be combined with EAAT2 studies to determine whether EAAT2 adapts to glutamate, or whether differential EAAT2 expression shifts the glutamatergic signaling system [86]. Arguably, induced animal models of depression best mimic environmentally induced adjustment disorders in humans and may not reflect the same biological mechanisms as primary mood disorders in human subjects. However, the most common findings in human and animal depression models were decreased EAAT2/Glt-1. A small number of animal studies reported Glt-1 upregulation in response to stress/corticosterone, perhaps reflecting an adaptive Glt-1 response to glutamate neurotoxicity. EAAT2 increases and decreases may reflect different experimental chronic stress duration, time of measurement since last stress exposure (i.e., acute stress response superimposed on chronic stress), and in at least one study, strain-specific differences in glutamatergic systems [37]. MRS studies are scarce in rodents, but comparison of glutamate levels with Glt-1 mRNA/protein levels would help clarify whether Glt-1 function and expression adapt to glutamate fluctuations as hypothesized.

A recent functional brain imaging study uncovered an interaction between SLC1A2 polymorphisms and ACE severity upon axial diffusion (along axonal fiber axis) in white matter tracts of BD patients [87]. This is important evidence for the role of glutamate in brain structural changes in response to stress. If stress and depression are associated with decreased glutamate concentrations, as human MRS studies have suggested, EAAT2/Glt-1 downregulation may be an adaptive glial transcriptional and/or translational response to reduced synaptic glutamate concentrations and subsequent reduced need for glutamate clearance. Glutamate reduction may be secondary either to absolute decreased glutamate levels (such as recycling back to glutamine and/or reduced glutamate synthesis) or decreased presynaptic glutamate release. Another mechanism of EAAT2/Glt-1 reduction might involve decreased glial fibrillary acidic protein (GFAP), a filament protein within astrocytes associated with EAAT2 cell membrane trafficking [88]. Consistent with this mechanism, elderly depressed and suicide subjects have demonstrated decreased GFAP [89, 90].

EAAT2 and AQP4 form a macromolecular complex and co-express with multiple other membrane proteins, as well as mitochondria and glycolytic enzymes [18]. In addition to regulating water and ion homeostasis of the neurovascular unit [91], AQP4 may significantly modulate astrocytic function and adult neurogenesis in depression. It has been previously noted that AQP4 rodent knockouts lose both the fluoxetine-induced antidepressant effect and hippocampus neurogenesis [92] and have greater depressive behaviors in response to chronic corticosterone administration [17]. The co-regulation of EAAT2 and AQP4 in mood disorders needs future investigation.

We found no study that reviewed the effect of antipsychotics on EAAT2 expression in human mood disorders. This is relevant because chronic antipsychotic exposure in primates has been associated with decreased brain volume [93] and decreased glial numbers [94]. Chronic antipsychotics in rodents have been associated with decreased Glt-1 [95], which might be secondary to glial decreases. These data are pertinent to future human studies of EAAT2 in mood disorders, as antipsychotics are clinically used for mood stabilization and as adjunctive therapy of depressive and anxious symptoms.

Individual SNPs are difficult to associate with mood disorders across genetic studies, partly reflecting the complexity of the pathophysiology of these conditions and partly the need for very large samples for adequate power. Human studies have suggested genetic and epigenetic contributions to BD and MDD, including differential expression of the SLC1A2 gene. Our group, for example, has studied epigenetic modifications of CpG islands in SLC1A2 promoter regions in BD with and without comorbid substance or food addictions [53]. BD was associated with hypermethylation, while BD + comorbid addictions were associated with hypomethylation, and the effect of addiction on epigenetic modulation of psychiatric disorders remains an area of ongoing research. Human studies have generally reported that MDD is associated with decreased SLC1A2 gene expression in most brain regions, but this has not been replicated in all brain regions, patient cohorts, or cortical layers. One study reported EAAT2 immunostaining was most pronounced in cortical layer II [57], a layer with high intracortical connectivity; the significance of this relationship requires further exploration. Studies have not reported significant associations between BD and SLC1A2 expression, except one reporting increased SLC1A2[62]. A difficulty with the human studies reviewed is that they report weak associations and are frequently not corrected for multiple testing. This is especially important in studies of microarray data. Additionally, our systematic process found no studies of gene expression in similar populations/brain regions explicitly reporting negative findings of SLC1A2, leading to a potential bias towards positive or false-positive findings.

While unipolar depression seems to be associated with decreased SLC1A2 gene and EAAT2/Glt-1 protein expression, no clear conclusion on the role of EAAT2 in BD can be drawn from the current data, pointing towards varying contributions of EAAT2 to the pathophysiology of different psychiatric disorders. Significant mechanistic questions remain, including the effect of brain regions and regional neural networks, genetic influences on glutamatergic regulation, and glial number. The involvement of EAAT2, not only in preventing excitotoxicity but also as part of a localized macromolecular complex, suggests that EAAT2 may be part of a complicated regulatory system, affecting not just glutamatergic pathways but also glial and neuronal cell homeostasis [96].

Future Perspectives

An increase in the understanding of the role of EAAT2 in mood disorders is highly warranted. Future studies could include the following areas of research: correlating EAAT2 with glutamatergic markers in vivo, comparing EAAT2 protein/mRNA expression in unipolar depressive disorders during depressive episodes and in remission, and in BD between manic/hypomanic, euthymic, and depressive mood states. Further understanding of the roles of the components of the macromolecular complex may also prove highly beneficial to elucidating roles and mechanisms of action of EAAT2.

The authors have no ethical conflicts to disclose.

The authors have no conflicts of interest to declare.

This research received no specific grant funding from the public, commercial, or not-for-profit sectors.

C.J.B. and M.V. conceived and designed the study. C.J.B., L.M.W., V.M., A.M.C.H., and M.V. performed data extraction. C.J.B. and L.M.W. undertook quality analysis. All authors provided critical feedback and participated in analysis and manuscript content. M.S., M.A.F., and M.V. supervised the project.

1.
World Health Organisation
.
Depression and Other Common Mental Disorders: Global Health Estimates
.
Geneva
:
World Health Organization
;
2017
. pp.
1
24
.
2.
Merikangas
KR
,
Jin
R
,
He
JP
,
Kessler
RC
,
Lee
S
,
Sampson
NA
, et al
.
Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative
.
Arch Gen Psychiatry
.
2011
Mar
;
68
(
3
):
241
51
.
[PubMed]
0003-990X
3.
Abdallah
CG
,
Jiang
L
,
De Feyter
HM
,
Fasula
M
,
Krystal
JH
,
Rothman
DL
, et al
.
Glutamate metabolism in major depressive disorder
.
Am J Psychiatry
.
2014
Dec
;
171
(
12
):
1320
7
.
[PubMed]
0002-953X
4.
Blacker
CJ
,
Lewis
CP
,
Frye
MA
,
Veldic
M
.
Metabotropic glutamate receptors as emerging research targets in bipolar disorder
.
Psychiatry Res
.
2017
Nov
;
257
:
327
37
.
[PubMed]
0165-1781
5.
Schousboe
A
.
Metabolic signaling in the brain and the role of astrocytes in control of glutamate and GABA neurotransmission
.
Neurosci Lett
.
2019
Jan
;
689
:
11
3
.
[PubMed]
0304-3940
6.
Kawahara
K
,
Hosoya
R
,
Sato
H
,
Tanaka
M
,
Nakajima
T
,
Iwabuchi
S
.
Selective blockade of astrocytic glutamate transporter GLT-1 with dihydrokainate prevents neuronal death during ouabain treatment of astrocyte/neuron cocultures
.
Glia
.
2002
Dec
;
40
(
3
):
337
49
.
[PubMed]
0894-1491
7.
Lauriat
TL
,
McInnes
LA
.
EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders
.
Mol Psychiatry
.
2007
Dec
;
12
(
12
):
1065
78
.
[PubMed]
1359-4184
8.
Takahashi
K
,
Foster
JB
,
Lin
CL
.
Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease
.
Cell Mol Life Sci
.
2015
Sep
;
72
(
18
):
3489
506
.
[PubMed]
1420-682X
9.
Bjørnsen
LP
,
Hadera
MG
,
Zhou
Y
,
Danbolt
NC
,
Sonnewald
U
.
The GLT-1 (EAAT2; slc1a2) glutamate transporter is essential for glutamate homeostasis in the neocortex of the mouse
.
J Neurochem
.
2014
Mar
;
128
(
5
):
641
9
.
[PubMed]
0022-3042
10.
Bjørn-Yoshimoto
WE
,
Underhill
SM
.
The importance of the excitatory amino acid transporter 3 (EAAT3)
.
Neurochem Int
.
2016
Sep
;
98
:
4
18
.
[PubMed]
0197-0186
11.
Rong
X
,
Tan
F
,
Wu
X
,
Zhang
X
,
Lu
L
,
Zou
X
, et al
.
TM4 of the glutamate transporter GLT-1 experiences substrate-induced motion during the transport cycle
.
Sci Rep
.
2016
Oct
;
6
(
34522
):
34522
. ;
Epub
.
[PubMed]
2045-2322
12.
Yernool
D
,
Boudker
O
,
Jin
Y
,
Gouaux
E
.
Structure of a glutamate transporter homologue from Pyrococcus horikoshii
.
Nature
.
2004
Oct
;
431
(
7010
):
811
8
.
[PubMed]
0028-0836
13.
Leary
GP
,
Stone
EF
,
Holley
DC
,
Kavanaugh
MP
.
The glutamate and chloride permeation pathways are colocalized in individual neuronal glutamate transporter subunits
.
J Neurosci
.
2007
Mar
;
27
(
11
):
2938
42
.
[PubMed]
0270-6474
14.
Qu
S
,
Kanner
BI
.
Substrates and non-transportable analogues induce structural rearrangements at the extracellular entrance of the glial glutamate transporter GLT-1/EAAT2
.
J Biol Chem
.
2008
Sep
;
283
(
39
):
26391
400
.
[PubMed]
0021-9258
15.
Jiang
J
,
Amara
SG
.
New views of glutamate transporter structure and function: advances and challenges
.
Neuropharmacology
.
2011
Jan
;
60
(
1
):
172
81
.
[PubMed]
0028-3908
16.
Hinson
SR
,
Roemer
SF
,
Lucchinetti
CF
,
Fryer
JP
,
Kryzer
TJ
,
Chamberlain
JL
, et al
.
Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2
.
J Exp Med
.
2008
Oct
;
205
(
11
):
2473
81
.
[PubMed]
0022-1007
17.
Kong
H
,
Zeng
XN
,
Fan
Y
,
Yuan
ST
,
Ge
S
,
Xie
WP
, et al
.
Aquaporin-4 knockout exacerbates corticosterone-induced depression by inhibiting astrocyte function and hippocampal neurogenesis
.
CNS Neurosci Ther
.
2014
May
;
20
(
5
):
391
402
.
[PubMed]
1755-5930
18.
Wang
H
,
Wang
S
,
Zhang
K
,
Wang
H
,
Lan
L
,
Ma
X
, et al
.
Aquaporin 4 Forms a Macromolecular Complex with Glutamate Transporter 1 and Mu Opioid Receptor in Astrocytes and Participates in Morphine Dependence
.
J Mol Neurosci
.
2017
May
;
62
(
1
):
17
27
.
[PubMed]
0895-8696
19.
Hubbard
JA
,
Szu
JI
,
Yonan
JM
,
Binder
DK
.
Regulation of astrocyte glutamate transporter-1 (GLT1) and aquaporin-4 (AQP4) expression in a model of epilepsy
.
Exp Neurol
.
2016
Sep
;
283
Pt A
:
85
96
.
[PubMed]
0014-4886
20.
Meyer
T
,
Münch
C
,
Liebau
S
,
Fromm
A
,
Schwalenstöcker
B
,
Völkel
H
, et al
.
Splicing of the glutamate transporter EAAT2: a candidate gene of amyotrophic lateral sclerosis
.
J Neurol Neurosurg Psychiatry
.
1998
Dec
;
65
(
6
):
954
.
[PubMed]
0022-3050
21.
Berger
UV
,
DeSilva
TM
,
Chen
W
,
Rosenberg
PA
.
Cellular and subcellular mRNA localization of glutamate transporter isoforms GLT1a and GLT1b in rat brain by in situ hybridization
.
J Comp Neurol
.
2005
Nov
;
492
(
1
):
78
89
.
[PubMed]
0021-9967
22.
Gourley
SL
,
Espitia
JW
,
Sanacora
G
,
Taylor
JR
.
Antidepressant-like properties of oral riluzole and utility of incentive disengagement models of depression in mice
.
Psychopharmacology (Berl)
.
2012
Feb
;
219
(
3
):
805
14
.
[PubMed]
0033-3158
23.
Guan
Y
,
Liu
X
,
Su
Y
.
Ceftriaxone pretreatment reduces the propensity of postpartum depression following stroke during pregnancy in rats
.
Neurosci Lett
.
2016
Oct
;
632
:
15
22
.
[PubMed]
0304-3940
24.
Abulseoud
OA
,
Camsari
UM
,
Ruby
CL
,
Kasasbeh
A
,
Choi
S
,
Choi
DS
.
Attenuation of ethanol withdrawal by ceftriaxone-induced upregulation of glutamate transporter EAAT2
.
Neuropsychopharmacology
.
2014
Jun
;
39
(
7
):
1674
84
.
[PubMed]
0893-133X
25.
Reagan
LP
,
Rosell
DR
,
Wood
GE
,
Spedding
M
,
Muñoz
C
,
Rothstein
J
, et al
.
Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus: reversal by tianeptine
.
Proc Natl Acad Sci USA
.
2004
Feb
;
101
(
7
):
2179
84
.
[PubMed]
0027-8424
26.
Wood
GE
,
Young
LT
,
Reagan
LP
,
Chen
B
,
McEwen
BS
.
Stress-induced structural remodeling in hippocampus: prevention by lithium treatment
.
Proc Natl Acad Sci USA
.
2004
Mar
;
101
(
11
):
3973
8
.
[PubMed]
0027-8424
27.
Pines
G
,
Danbolt
NC
,
Bjørås
M
,
Zhang
Y
,
Bendahan
A
,
Eide
L
, et al
.
Cloning and expression of a rat brain L-glutamate transporter
.
Nature
.
1992
Dec
;
360
(
6403
):
464
7
.
[PubMed]
0028-0836
28.
Bechtholt-Gompf
AJ
,
Walther
HV
,
Adams
MA
,
Carlezon
WA
Jr
,
Ongür
D
,
Cohen
BM
.
Blockade of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory
.
Neuropsychopharmacology
.
2010
Sep
;
35
(
10
):
2049
59
.
[PubMed]
0893-133X
29.
Chen
JX
,
Yao
LH
,
Xu
BB
,
Qian
K
,
Wang
HL
,
Liu
ZC
, et al
.
Glutamate transporter 1-mediated antidepressant-like effect in a rat model of chronic unpredictable stress
.
J Huazhong Univ Sci Technolog Med Sci
.
2014
Dec
;
34
(
6
):
838
44
.
[PubMed]
1672-0733
30.
Cui
W
,
Mizukami
H
,
Yanagisawa
M
,
Aida
T
,
Nomura
M
,
Isomura
Y
, et al
.
Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance
.
J Neurosci
.
2014
Dec
;
34
(
49
):
16273
85
.
[PubMed]
0270-6474
31.
Gasull-Camós
J
,
Tarrés-Gatius
M
,
Artigas
F
,
Castañé
A
.
Glial GLT-1 blockade in infralimbic cortex as a new strategy to evoke rapid antidepressant-like effects in rats
.
Transl Psychiatry
.
2017
Feb
;
7
(
2
e1038
):
e1038
. ;
Epub
.
[PubMed]
2158-3188
32.
Gómez-Galán
M
,
Femenía
T
,
Åberg
E
,
Graae
L
,
Van Eeckhaut
A
,
Smolders
I
, et al
.
Running Opposes the Effects of Social Isolation on Synaptic Plasticity and Transmission in a Rat Model of Depression
.
PLoS One
.
2016
Oct
;
11
(
10
e0165071
):
e0165071
. ;
Epub
.
[PubMed]
1932-6203
33.
John
CS
,
Sypek
EI
,
Carlezon
WA
,
Cohen
BM
,
Öngür
D
,
Bechtholt
AJ
.
Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms
.
Neuropsychopharmacology
.
2015
Jun
;
40
(
7
):
1700
8
.
[PubMed]
0893-133X
34.
Kang
S
,
Li
J
,
Bekker
A
,
Ye
JH
.
Rescue of glutamate transport in the lateral habenula alleviates depression- and anxiety-like behaviors in ethanol-withdrawn rats
.
Neuropharmacology
.
2018
Feb
;
129
:
47
56
.
[PubMed]
0028-3908
35.
Liu
WX
,
Wang
J
,
Xie
ZM
,
Xu
N
,
Zhang
GF
,
Jia
M
, et al
.
Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression
.
Psychopharmacology (Berl)
.
2016
Feb
;
233
(
3
):
405
15
.
[PubMed]
0033-3158
36.
Liu
X
,
Guo
H
,
Sayed
MD
,
Lu
Y
,
Yang
T
,
Zhou
D
, et al
.
cAMP/PKA/CREB/GLT1 signaling involved in the antidepressant-like effects of phosphodiesterase 4D inhibitor (GEBR-7b) in rats
.
Neuropsychiatr Dis Treat
.
2016
Jan
;
12
:
219
27
.
[PubMed]
1176-6328
37.
Malki
K
,
Lourdusamy
A
,
Binder
E
,
Payá-Cano
J
,
Sluyter
F
,
Craig
I
, et al
.
Antidepressant-dependent mRNA changes in mouse associated with hippocampal neurogenesis in a mouse model of depression
.
Pharmacogenet Genomics
.
2012
Nov
;
22
(
11
):
765
76
.
[PubMed]
1744-6872
38.
Manosso
LM
,
Moretti
M
,
Colla
AR
,
Ribeiro
CM
,
Dal-Cim
T
,
Tasca
CI
, et al
.
Involvement of glutamatergic neurotransmission in the antidepressant-like effect of zinc in the chronic unpredictable stress model of depression
.
J Neural Transm (Vienna)
.
2016
Mar
;
123
(
3
):
339
52
.
[PubMed]
0300-9564
39.
Martisova
E
,
Solas
M
,
Horrillo
I
,
Ortega
JE
,
Meana
JJ
,
Tordera
RM
, et al
.
Long lasting effects of early-life stress on glutamatergic/GABAergic circuitry in the rat hippocampus
.
Neuropharmacology
.
2012
Apr
;
62
(
5-6
):
1944
53
.
[PubMed]
0028-3908
40.
Rappeneau
V
,
Blaker
A
,
Petro
JR
,
Yamamoto
BK
,
Shimamoto
A
.
Disruption of the Glutamate-Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females
.
Front Behav Neurosci
.
2016
Dec
;
10
(
231
):
231
. ;
Epub
.
[PubMed]
1662-5153
41.
Réus
GZ
,
Abaleira
HM
,
Michels
M
,
Tomaz
DB
,
dos Santos
MA
,
Carlessi
AS
, et al
.
Anxious phenotypes plus environmental stressors are related to brain DNA damage and changes in NMDA receptor subunits and glutamate uptake
.
Mutat Res
.
2015
Feb
;
772
:
30
7
.
[PubMed]
0027-5107
42.
Veeraiah
P
,
Noronha
JM
,
Maitra
S
,
Bagga
P
,
Khandelwal
N
,
Chakravarty
S
, et al
.
Dysfunctional glutamatergic and γ-aminobutyric acidergic activities in prefrontal cortex of mice in social defeat model of depression
.
Biol Psychiatry
.
2014
Aug
;
76
(
3
):
231
8
.
[PubMed]
0006-3223
43.
Zhang
XH
,
Jia
N
,
Zhao
XY
,
Tang
GK
,
Guan
LX
,
Wang
D
, et al
.
Involvement of pGluR1, EAAT2 and EAAT3 in offspring depression induced by prenatal stress
.
Neuroscience
.
2013
Oct
;
250
:
333
41
.
[PubMed]
0306-4522
44.
Zhang
X
,
Sun
H
,
Su
Q
,
Lin
T
,
Zhang
H
,
Zhang
J
, et al
.
Antidepressant-like activity of icariin mediated by group I mGluRs in prenatally stressed offspring
.
Brain Dev
.
2017
Aug
;
39
(
7
):
593
600
.
[PubMed]
0387-7604
45.
Zhu
X
,
Hao
X
,
Luo
J
,
Min
S
,
Xie
F
,
Zhang
F
.
Propofol inhibits inflammatory cytokine-mediated glutamate uptake dysfunction to alleviate learning/memory impairment in depressed rats undergoing electroconvulsive shock
.
Brain Res
.
2015
Jan
;
1595
:
101
9
.
[PubMed]
0006-8993
46.
Zhu
X
,
Ye
G
,
Wang
Z
,
Luo
J
,
Hao
X
.
Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats
.
Neurosci Lett
.
2017
Feb
;
639
:
132
7
.
[PubMed]
0304-3940
47.
Zink
M
,
Vollmayr
B
,
Gebicke-Haerter
PJ
,
Henn
FA
.
Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression
.
Neuropharmacology
.
2010
Feb
;
58
(
2
):
465
73
.
[PubMed]
0028-3908
48.
Bernard
R
,
Kerman
IA
,
Thompson
RC
,
Jones
EG
,
Bunney
WE
,
Barchas
JD
, et al
.
Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression
.
Mol Psychiatry
.
2011
Jun
;
16
(
6
):
634
46
.
[PubMed]
1359-4184
49.
Chandley
MJ
,
Szebeni
K
,
Szebeni
A
,
Crawford
J
,
Stockmeier
CA
,
Turecki
G
, et al
.
Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder
.
J Psychiatry Neurosci
.
2013
Jul
;
38
(
4
):
276
84
.
[PubMed]
1180-4882
50.
Choudary
PV
,
Molnar
M
,
Evans
SJ
,
Tomita
H
,
Li
JZ
,
Vawter
MP
, et al
.
Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression
.
Proc Natl Acad Sci USA
.
2005
Oct
;
102
(
43
):
15653
8
.
[PubMed]
0027-8424
51.
Dallaspezia
S
,
Poletti
S
,
Lorenzi
C
,
Pirovano
A
,
Colombo
C
,
Benedetti
F
.
Influence of an interaction between lithium salts and a functional polymorphism in SLC1A2 on the history of illness in bipolar disorder
.
Mol Diagn Ther
.
2012
Oct
;
16
(
5
):
303
9
.
[PubMed]
1177-1062
52.
Fiorentino
A
,
Sharp
SI
,
McQuillin
A
.
Association of rare variation in the glutamate receptor gene SLC1A2 with susceptibility to bipolar disorder and schizophrenia
.
Eur J Hum Genet
.
2015
Sep
;
23
(
9
):
1200
6
.
[PubMed]
1018-4813
53.
Jia
YF
,
Choi
Y
,
Ayers-Ringler
JR
,
Biernacka
JM
,
Geske
JR
,
Lindberg
DR
, et al
.
Differential SLC1A2 Promoter Methylation in Bipolar Disorder With or Without Addiction
.
Front Cell Neurosci
.
2017
Jul
;
11
(
217
):
217
. ;
Epub
.
[PubMed]
1662-5102
54.
McCullumsmith
RE
,
Meador-Woodruff
JH
.
Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder
.
Neuropsychopharmacology
.
2002
Mar
;
26
(
3
):
368
75
.
[PubMed]
0893-133X
55.
Medina
A
,
Burke
S
,
Thompson
RC
,
Bunney
W
Jr
,
Myers
RM
,
Schatzberg
A
, et al
.
Glutamate transporters: a key piece in the glutamate puzzle of major depressive disorder
.
J Psychiatr Res
.
2013
Sep
;
47
(
9
):
1150
6
.
[PubMed]
0022-3956
56.
Medina
A
,
Watson
SJ
,
Bunney
W
Jr
,
Myers
RM
,
Schatzberg
A
,
Barchas
J
, et al
.
Evidence for alterations of the glial syncytial function in major depressive disorder
.
J Psychiatr Res
.
2016
Jan
;
72
:
15
21
.
[PubMed]
0022-3956
57.
Miguel-Hidalgo
JJ
,
Waltzer
R
,
Whittom
AA
,
Austin
MC
,
Rajkowska
G
,
Stockmeier
CA
.
Glial and glutamatergic markers in depression, alcoholism, and their comorbidity
.
J Affect Disord
.
2010
Dec
;
127
(
1-3
):
230
40
.
[PubMed]
0165-0327
58.
Murphy
TM
,
Ryan
M
,
Foster
T
,
Kelly
C
,
McClelland
R
,
O’Grady
J
, et al
.
Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms
.
Behav Brain Funct
.
2011
Jun
;
7
(
22
):
22
. ;
Epub
.
[PubMed]
1744-9081
59.
Oh
DH
,
Oh
D
,
Son
H
,
Webster
MJ
,
Weickert
CS
,
Kim
SH
.
An association between the reduced levels of SLC1A2 and GAD1 in the dorsolateral prefrontal cortex in major depressive disorder: possible involvement of an attenuated RAF/MEK/ERK signaling pathway
.
J Neural Transm (Vienna)
.
2014
Jul
;
121
(
7
):
783
92
.
[PubMed]
0300-9564
60.
Poletti
S
,
Locatelli
C
,
Pirovano
A
,
Colombo
C
,
Benedetti
F
.
Glutamate EAAT1 transporter genetic variants influence cognitive deficits in bipolar disorder
.
Psychiatry Res
.
2015
Mar
;
226
(
1
):
407
8
.
[PubMed]
0165-1781
61.
Poletti
S
,
Locatelli
C
,
Radaelli
D
,
Lorenzi
C
,
Smeraldi
E
,
Colombo
C
, et al
.
Effect of early stress on hippocampal gray matter is influenced by a functional polymorphism in EAAT2 in bipolar disorder
.
Prog Neuropsychopharmacol Biol Psychiatry
.
2014
Jun
;
51
:
146
52
.
[PubMed]
0278-5846
62.
Shao
L
,
Vawter
MP
.
Shared gene expression alterations in schizophrenia and bipolar disorder
.
Biol Psychiatry
.
2008
Jul
;
64
(
2
):
89
97
.
[PubMed]
0006-3223
63.
Zhao
J
,
Verwer
RW
,
van Wamelen
DJ
,
Qi
XR
,
Gao
SF
,
Lucassen
PJ
, et al
.
Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide
.
J Psychiatr Res
.
2016
Nov
;
82
:
8
15
.
[PubMed]
0022-3956
64.
du Prel
JB
,
Röhrig
B
,
Blettner
M
.
Critical appraisal of scientific articles: part 1 of a series on evaluation of scientific publications
.
Dtsch Arztebl Int
.
2009
Feb
;
106
(
7
):
100
5
.
[PubMed]
1866-0452
65.
Henn
FA
,
Vollmayr
B
.
Stress models of depression: forming genetically vulnerable strains
.
Neurosci Biobehav Rev
.
2005
;
29
(
4-5
):
799
804
.
[PubMed]
0149-7634
66.
Popoli
M
,
Yan
Z
,
McEwen
BS
,
Sanacora
G
.
The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission
.
Nat Rev Neurosci
.
2011
Nov
;
13
(
1
):
22
37
.
[PubMed]
1471-003X
67.
Behan
ÁT
,
van den Hove
DL
,
Mueller
L
,
Jetten
MJ
,
Steinbusch
HW
,
Cotter
DR
, et al
.
Evidence of female-specific glial deficits in the hippocampus in a mouse model of prenatal stress
.
Eur Neuropsychopharmacol
.
2011
Jan
;
21
(
1
):
71
9
.
[PubMed]
0924-977X
68.
Laschet
J
,
Grisar
T
,
Bureau
M
,
Guillaume
D
.
Characteristics of putrescine uptake and subsequent GABA formation in primary cultured astrocytes from normal C57BL/6J and epileptic DBA/2J mouse brain cortices
.
Neuroscience
.
1992
;
48
(
1
):
151
7
.
[PubMed]
0306-4522
69.
Bobo
WV
,
Vande Voort
JL
,
Croarkin
PE
,
Leung
JG
,
Tye
SJ
,
Frye
MA
.
Ketamine for Treatment-Resistant Unipolar and Bipolar Major Depression: Critical Review and Implications for Clinical Practice
.
Depress Anxiety
.
2016
Aug
;
33
(
8
):
698
710
.
[PubMed]
1091-4269
70.
Wray
NR
,
Ripke
S
,
Mattheisen
M
,
Trzaskowski
M
,
Byrne
EM
,
Abdellaoui
A
, et al;
eQTLGen
;
23andMe
;
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
.
Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression
.
Nat Genet
.
2018
May
;
50
(
5
):
668
81
.
[PubMed]
1061-4036
71.
Stahl
EA
,
Breen
G
,
Forstner
AJ
,
McQuillin
A
,
Ripke
S
,
Trubetskoy
V
, et al;
eQTLGen Consortium
;
BIOS Consortium
;
Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
.
Genome-wide association study identifies 30 loci associated with bipolar disorder
.
Nat Genet
.
2019
May
;
51
(
5
):
793
803
.
[PubMed]
1061-4036
72.
Ruderfer
DM
,
Ripke
S
,
McQuillin
A
,
Boocock
J
,
Stahl
EA
,
Pavlides
JM
, et al;
Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address: douglas.ruderfer@vanderbilt.edu
;
Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium
.
Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes
.
Cell
.
2018
Jun
;
173
(
7
):
1705
1715.e16
.
[PubMed]
0092-8674
73.
Veldic
M
,
Millischer
V
,
Port
JD
,
Ho
AM
,
Jia
YF
,
Geske
JR
, et al
.
Genetic variant in SLC1A2 is associated with elevated anterior cingulate cortex glutamate and lifetime history of rapid cycling
.
Transl Psychiatry
.
2019
May
;
9
(
1
):
149
.
[PubMed]
2158-3188
74.
de Sousa
RT
,
Loch
AA
,
Carvalho
AF
,
Brunoni
AR
,
Haddad
MR
,
Henter
ID
, et al
.
Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders
.
Neuropsychopharmacology
.
2017
Mar
;
42
(
4
):
787
800
.
[PubMed]
0893-133X
75.
Parkin
GM
,
Udawela
M
,
Gibbons
A
,
Dean
B
.
Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders
.
World J Psychiatry
.
2018
Jun
;
8
(
2
):
51
63
.
[PubMed]
2220-3206
76.
Mallolas
J
,
Hurtado
O
,
Castellanos
M
,
Blanco
M
,
Sobrino
T
,
Serena
J
, et al
.
A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke
.
J Exp Med
.
2006
Mar
;
203
(
3
):
711
7
.
[PubMed]
0022-1007
77.
Teffer
K
,
Semendeferi
K
.
Human prefrontal cortex: evolution, development, and pathology
.
Prog Brain Res
.
2012
;
195
:
191
218
.
[PubMed]
0079-6123
78.
Shenhav
A
,
Botvinick
MM
,
Cohen
JD
.
The expected value of control: an integrative theory of anterior cingulate cortex function
.
Neuron
.
2013
Jul
;
79
(
2
):
217
40
.
[PubMed]
0896-6273
79.
Mai
J
,
Paxinos
G
, editors
.
The Human Nervous System
. 3rd ed.
San Diego
:
Academic Press
;
2012
.
80.
Castillo
J
,
Loza
MI
,
Mirelman
D
,
Brea
J
,
Blanco
M
,
Sobrino
T
, et al
.
A novel mechanism of neuroprotection: blood glutamate grabber
.
J Cereb Blood Flow Metab
.
2016
Feb
;
36
(
2
):
292
301
.
[PubMed]
0271-678X
81.
Rao
VL
,
Başkaya
MK
,
Doğan
A
,
Rothstein
JD
,
Dempsey
RJ
.
Traumatic brain injury down-regulates glial glutamate transporter (GLT-1 and GLAST) proteins in rat brain
.
J Neurochem
.
1998
May
;
70
(
5
):
2020
7
.
[PubMed]
0022-3042
82.
Lai
TW
,
Zhang
S
,
Wang
YT
.
Excitotoxicity and stroke: identifying novel targets for neuroprotection
.
Prog Neurobiol
.
2014
Apr
;
115
:
157
88
.
[PubMed]
0301-0082
83.
Terasaki
Y
,
Liu
Y
,
Hayakawa
K
,
Pham
LD
,
Lo
EH
,
Ji
X
, et al
.
Mechanisms of neurovascular dysfunction in acute ischemic brain
.
Curr Med Chem
.
2014
;
21
(
18
):
2035
42
.
[PubMed]
0929-8673
84.
Plitman
E
,
Nakajima
S
,
de la Fuente-Sandoval
C
,
Gerretsen
P
,
Chakravarty
MM
,
Kobylianskii
J
, et al
.
Glutamate-mediated excitotoxicity in schizophrenia: a review
.
Eur Neuropsychopharmacol
.
2014
Oct
;
24
(
10
):
1591
605
.
[PubMed]
0924-977X
85.
Plitman
E
,
de la Fuente-Sandoval
C
,
Reyes-Madrigal
F
,
Chavez
S
,
Gómez-Cruz
G
,
León-Ortiz
P
, et al
.
Elevated Myo-Inositol, Choline, and Glutamate Levels in the Associative Striatum of Antipsychotic-Naive Patients With First-Episode Psychosis: A Proton Magnetic Resonance Spectroscopy Study With Implications for Glial Dysfunction
.
Schizophr Bull
.
2016
Mar
;
42
(
2
):
415
24
.
[PubMed]
0586-7614
86.
Yüksel
C
,
Öngür
D
.
Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders
.
Biol Psychiatry
.
2010
Nov
;
68
(
9
):
785
94
.
[PubMed]
0006-3223
87.
Poletti
S
,
Bollettini
I
,
Lorenzi
C
,
Vitali
A
,
Brioschi
S
,
Serretti
A
, et al
.
White Matter Microstructure in Bipolar Disorder Is Influenced by the Interaction between a Glutamate Transporter EAAT1 Gene Variant and Early Stress
.
Mol Neurobiol
.
2019
Jan
;
56
(
1
):
702
10
.
[PubMed]
0893-7648
88.
Hughes
EG
,
Maguire
JL
,
McMinn
MT
,
Scholz
RE
,
Sutherland
ML
.
Loss of glial fibrillary acidic protein results in decreased glutamate transport and inhibition of PKA-induced EAAT2 cell surface trafficking
.
Brain Res Mol Brain Res
.
2004
May
;
124
(
2
):
114
23
.
[PubMed]
0169-328X
89.
Davis
S
,
Thomas
A
,
Perry
R
,
Oakley
A
,
Kalaria
RN
,
O’Brien
JT
.
Glial fibrillary acidic protein in late life major depressive disorder: an immunocytochemical study
.
J Neurol Neurosurg Psychiatry
.
2002
Nov
;
73
(
5
):
556
60
.
[PubMed]
0022-3050
90.
Torres-Platas
SG
,
Nagy
C
,
Wakid
M
,
Turecki
G
,
Mechawar
N
.
Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides
.
Mol Psychiatry
.
2016
Apr
;
21
(
4
):
509
15
.
[PubMed]
1359-4184
91.
Rajkowska
G
,
Stockmeier
CA
.
Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue
.
Curr Drug Targets
.
2013
Oct
;
14
(
11
):
1225
36
.
[PubMed]
1389-4501
92.
Kong
H
,
Sha
LL
,
Fan
Y
,
Xiao
M
,
Ding
JH
,
Wu
J
, et al
.
Requirement of AQP4 for antidepressive efficiency of fluoxetine: implication in adult hippocampal neurogenesis
.
Neuropsychopharmacology
.
2009
Apr
;
34
(
5
):
1263
76
.
[PubMed]
0893-133X
93.
Dorph-Petersen
KA
,
Pierri
JN
,
Perel
JM
,
Sun
Z
,
Sampson
AR
,
Lewis
DA
.
The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys
.
Neuropsychopharmacology
.
2005
Sep
;
30
(
9
):
1649
61
.
[PubMed]
0893-133X
94.
Konopaske
GT
,
Dorph-Petersen
KA
,
Sweet
RA
,
Pierri
JN
,
Zhang
W
,
Sampson
AR
, et al
.
Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys
.
Biol Psychiatry
.
2008
Apr
;
63
(
8
):
759
65
.
[PubMed]
0006-3223
95.
Schneider
JS
,
Wade
T
,
Lidsky
TI
.
Chronic neuroleptic treatment alters expression of glial glutamate transporter GLT-1 mRNA in the striatum
.
Neuroreport
.
1998
Jan
;
9
(
1
):
133
6
.
[PubMed]
0959-4965
96.
O’Donovan
SM
,
Sullivan
CR
,
McCullumsmith
RE
. The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders. npj Schizophrenia.
2017
;3,(32):1-14. doi: [Epub].