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Event: 1488

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Glutamate dyshomeostasis

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Glutamate dyshomeostasis

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Cellular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Cell term
neural cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term
brain

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Oxidative stress and Developmental impairment in learning and memory KeyEvent Marie-Gabrielle Zurich (send email) Under development: Not open for comment. Do not cite EAGMST Under Review

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Glutamate (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS), where it plays major roles in multiple aspects, such as development, learning, memory and response to injury (Featherstone, 2010). However, it is well recognized that Glu at high concentrations at the synaptic cleft acts as a toxin, inducing neuronal injury and death (Meldrum, 2000; Ozawa et al., 1998) secondary to activation of glumatergic N-methyl D-aspartate (NMDA) receptors and Ca2+ influx. Glu dyshomeostasis is a consequence of perturbation of  astrocyte/neuron interactions and the transport of this amino acid, as will be discussed below.

Astrocytes are critically involved in neuronal function and survival, as they produce neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and glia-derived neurotrophic factor (GDNF), as well as express two main glutamate transporters responsible for the removal of excessive Glu from the synaptic clefts (Chai et al., 2013; Sheldon et al., 2007). Glutamate is the major excitatory neurotransmitter in the CNS, playing a major role in memory and cognitive function (Platt, 1997), and Glu transporters as such prevent the overstimulation of post-synaptic glutamate receptors that lead to excitotoxic neuronal injury (Sattler et al., 2001; Dobble, 1999). Among the five subtypes of Glu transporters identified, glutamate aspartate transporter (GLAST) and Glu transporter-1 (GLT-1) [excitatory amino acid transporter (EAAT) 1 and 2 in humans, respectively], are predominantly expressed in astrocytes. They are responsible for the uptake of excess glutamate from the extracellular space (Furuta et al., 1997; Lehre et al., 1995; Tanaka, 2000), supported by the fact that knockdown of either GLT-1 or GLAST in mice increases extracellular glutamate levels, leading to excitotoxicity related neurodegeneration and progressive paralysis (Bristol and Rothstein, 1996). In the adult brain, EAAT2 accounts for >90% of extracellular glutamate clearance (Danbolt, 2001; Kim et al., 2011; Rothstein et al., 1995), and genetic deletion of both alleles of GLT-1 in mice leads to the development of lethal seizures (Rothstein et al., 1996). On the other hand, EAAT1-3 play a major role during human brain development, in particular in corticogenesis, where they are expressed in proliferative zones and in radial glia, and alterations of Glu transporters contributes to disorganized cortex seen in migration disorders (Furuta et al., 2005;Regan et al., 2007). Indeed, disruption of glutamate signaling is thought to be part of the etiology underlying some neurodevelopmental disorders such as autism and schizophrenia (Chiocchetti et al., 2014; Schwartz et al., 2012). Genes involved in glutamatergic pathways, affecting receptor signalling, metabolism and transport, were enriched in genetic variants associated with autism spectrum disorders (Chiocchetti et al, 2014).

Extracellular Glu released by neurons is taken up by astrocytes, which is converted into glutamine (Gln) by glutamine synthetase (GS), a thiol-containing enzyme (cf MIE, Binding to SH-/seleno containing proteins). Intercellular compartmentation of Gln and Glu, the so-called Gln/Glu-GABA cycle (GGC), is critical for optimal CNS function.13C NMR studies have demonstrated that the ratio of Gln/Glu is extremely high and increases with brain activity (Shen et al., 1999). Thus the GGC gives rise to the amino acid neurotransmitters Glu and GABA via dynamic astrocyte neuron interactions. Glu released at synaptic terminals is taken up by surrounding astrocytes via GLT-1 and GLAST (Rothstein et al., 1994; 1996). A small proportion of the astrocytic formed Gln via a reaction mediated by GS is transported into the extracellular space by Gln carriers, with a predominant role for System N/A transporter (SNAT3), which belongs to the bidirectional transporter System N (Chaudhry et al., 2002).

In addition to System N, release of Gln from astrocytes is mediated by other transport systems, including Systems L (LAT2) and ASC (ASCT2). Extracellular Gln is taken up into GABAergic and Glu-ergic neurons by the unidirectional System A transporters SNAT1 (Melone et al., 2004) and SNAT2 (Grewal et al., 2009). Once in neurons, Gln is converted to Glu by the mitochondrial enzyme phosphate-activated glutaminase (Kvamme et al., 2001). Additionally, Glu is packaged into synaptic vesicles by the vesicular VGLUT transporter (Bellocchio et al., 1998), released into the extracellular space and taken up by astrocytes where it is converted back to Gln by GS, thus completing the GGC (Fig. 1).

Figure 1: Schematic representation of Glu and Gln transport systems related to the GGC. From Sidorik-Wegrzynowicz and Aschner, 2013)

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

 L-Glu transporter activities can be quantified by direct or indirect methods:

・For direct quantification, L-Glu transporter activities are determined by the amount of 3H-labeled ligand (L-Glu or D-aspartate) taken up by the cells (Primary mixed astrocyte and neuron cultures [Perez-Dominguez et al., 2014]; primary astrocyte cultures [Matos et al., 2008; Li et al., 2006; Hazell et al., 2003]; Xenopus laevis oocyte overexpressing the L-Glu transporter subtype of interest [Sogaard et al., 2013; Trotti et al., 2001]; transfected HeLa cells [Zhang and Qu, 2012]) or tissues (ex. Hippocampal tissue [Selkirk et al., 2005])

・For indirect quantification, L-Glu transporter activities are determined by the L-Glu residue in the medium or buffer after incubation with cells expressing the different L-Glu transporters (Brison et al., 2014; Xin et al., 2019; Jin et al., 2015; Gu et al., 2014; Abe et alt.2000], .).

・The transport activity of the different L-Glu transporter subtypes should be determined in the presence of the appropriate inhibitors as shown in the table 1. Ex: The glutamate uptake activity via EAAT1 can be determined in the presence of dihydrokainic acid (DHK), a specific inhibitor for GLT-1, as described in Mutkus et al. (2005). Expression level of L-Glu transporter subtypes should be confirmed using Western blotting or immunocytochemistry.  It is interesting to note that pure astrocyte culture express only GLAST (EAAT1) (Danbolt et al., 2016); whereas  In mixed astrocyte and neuron cultures, GLAST (EAAT1) and GLT-1(EAAT2) are expressed (Danbolt et al., 2016). The expression of GLT1 (EAAT2) is suggested to be induced by soluble factors (Gegelashvili et al., 1997, 2000; Plachez et al., 2000; Martinez-Lozada et al., 2016).  

For measuring glutamate release, load 3H glutamate for several hours and then look at release over time, as descibed in (Arizza et al., 1994)

The L-Glu concentrations in medium or in incubation buffer can be quantified by commercially-available kits quantifying the final products of the redox reaction in which L-Glu is a substrate.   

The kits using colorimetric final products (OD=450 nm)

■Glutamate Assay Kit from Abcam (ab83389)

■Glutamate Colorimetric Assay Kit from BioVision (K629)

■Glutamate Assay Kit from Merck (MAK004)  

The kit using the bioluminescent metabolite

■Glutamate-Glo™ Assay from Promega (J7021)

Table 1 is a summary based on the reviews of Murphy-Royal et al., 2017 and Pajarillo et al., 2019, with some modification.  Concerning the physiological functions of each EAAT subtype, see the review by Danbolt (Danbolt, 2001).

human

rodent

distribution

Non-specific inhibitors

Specific inhibitors

EAAT1

GLAST

Astrocytes, cerebellum,

High expression in astrocytes at developmental stage

DL-threo-b-benzyloxyaspartate

(TBOA) and its variants (e.g. PMBTBOA

and TFB-TBOA) (Bridges et al.,

1999; Lebrun et al., 1997; Shimamoto et al., 1998; Shimamoto,

2008)

UCPH101 (Erichsen et al., 2010)

EAAT2

GLT-1

Astrocytes

(>90% adult CNS L-Glu uptake)

Neuronal terminals (hippocampus, cortex, still controversial)

WAY213613 (Dunlop et al., 2005)

DHK (Arriza et al.,

1994; Bridges et al., 1999

EAAT3

EAAC1

Neurons

Especially high in hippocampal neurons.

Also function as  Cys transporter (Watts et al., 2014)

EAAT4

EAAT4

Purkinje cells in the cerebellum

EAAT5

EAAT5

Retina,

Very weak in the CNS

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

The involvement of glutamate in learning and memory processes is well conserved in all taxa, from invertebrates (ex. Drosophila) to vertebrates (Fagnou and Tuchek, 1995).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

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Bridges RJ, Kavanaugh MP, Chamberlin AR. A pharmacological review of competitive inhibitors and substrates of high-affinity, sodium-dependent glutamate transport in the central nervous system. 1999; Curr. Pharm. Des. 5, 363e379.

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Chiocchetti, A. G., H. S. Bour and C. M. Freitag (2014). "Glutamatergic candidate genes in autism spectrum disorder: an overview." J Neural Transm (Vienna) 121(9): 1081-1106.

Danbolt NC. Glutamate uptake. Progress in neurobiology. 2001;65:1–105.

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Erichsen MN, Huynh TH, Abrahamsen B, Bastlund JF, Bundgaard C, Monrad O, Bekker-Jensen A, Nielsen CW, Frydenvang K, Jensen AA, Bunch L. Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101). J Med Chem. 2010 Oct 14;53(19):7180-91.

Fagnou DD, Tuchek JM (1995) The biochemistry of learning and memory. Mol Cell Biochem 149-150:279-86

Featherstone, D. E. (2010). "Intercellular glutamate signaling in the nervous system and beyond." ACS Chem Neurosci 1(1): 4-12.

Furuta A, Rothstein JD, Martin LJ. Glutamate transporter protein subtypes are expressed differentially during rat CNS development. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1997;17:8363–8375.

Furuta, A., S. Takashima, H. Yokoo, J. D. Rothstein, K. Wada and T. Iwaki (2005). "Expression of glutamate transporter subtypes during normal human corticogenesis and type II lissencephaly." Brain Res Dev Brain Res 155(2): 155-164.

Gegelashvili G, Danbolt NC, Schousboe A, Neuronal soluble factors differentially regulate the expression of the GLT1 and GLAST glutamate transporters in cultured astroglia. J. Neurochem. 1997; 69, 2612e2615.

Gegelashvili G, Dehnes Y, Danbolt NC, Schousboe A, The high-affinity glutamate transporters GLT1, GLAST and EAAT4 are regulated via different signalling mechanisms. Neurochem. Int. 2000; 37, 163e170.

Grewal S, Defamie N, Zhang X, et al. SNAT2 amino acid transporter is regulated by amino acids of the SLC6 gamma-aminobutyric acid transporter subfamily in neocortical neurons and may play no role in delivering glutamine for glutamatergic transmission. J Biol Chem. 2009;284:11224–36.

Gu L, Xu H, Wang F, Xu G, Sinha D, Wang J, Xu JY, Tian H, Gao F, Li W, Lu L, Zhang J, Xu GT, Erythropoietin Exerts a Neuroprotective Function Against Glutamate Neurotoxicity in Experimental Diabetic Retina. Invest. Ophthalmol. Vis. Sci., Dec 2014; 55: 8208 - 8222.

Hazell AS, Pannunzio P, Rama Rao KV, Pow DV, Rambaldi A. Thiamine deficiency results in downregulation of the GLAST glutamate transporter in cultured astrocytes. Glia. 2003 Aug;43(2):175-84.

Jin LW, Horiuchi M, Wulff H, Liu XB, Cortopassi GA, Erickson JD, Maezawa I., Rett Syndrome Microglia: A Mechanism for Mitochondrial Dysfunction and Neurotoxicity. J. Neurosci., Feb 2015; 35: 2516 – 2529

Kim K, Lee SG, Kegelman TP, Su ZZ, Das SK, Dash R, Dasgupta S, Barral PM, Hedvat M, Diaz P, Reed JC, Stebbins JL, Pellecchia M, Sarkar D, Fisher PB. Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. Journal of cellular physiology. 2011;226:2484–2493.

Kvamme E, Torgner IA, Roberg B. Kinetics and localization of brain phosphate activated glutaminase. J Neurosci Res. 2001;66:951–8.

Lebrun B, Sakaitani M, Shimamoto K, Yasudakamatani Y, Nakajima T, New beta-hydroxyaspartate derivatives are competitive blockers for the bovine glutamate/aspartate transporter. 1997; J. Biol. Chem. 272, 20336e20339.

Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1995;15:1835–1853.

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Melone M, Quagliano F, Barbaresi P, Varoqui H, Erickson JD, Conti F. Localization of the glutamine transporter SNAT1 in rat cerebral cortex and neighboring structures, with a note on its localization in human cortex. Cereb Cortex. 2004;14:562–74.

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Shimamoto K, Lebrun B, Yasudakamatani Y., Sakaitani M, Shigeri Y, Yumoto N, Nakajima T. DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters. 1998; Mol. Pharmacol. 53, 195e201.

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