To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KE:383

Event: 383

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

Reduced, Presynaptic release of glutamate

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
Reduced, Presynaptic release of glutamate

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
Molecular

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
neuron

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

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
Process Object Action
glutamate secretion glutamate(1-) decreased

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
Binding of antagonist to NMDARs impairs cognition KeyEvent Agnes Aggy (send email) Open for citation & comment TFHA/WNT Endorsed

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
Term Scientific Term Evidence Link
humans Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mice Mus sp. High NCBI

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

Biological state: Glutamate is an amino acid with neurotransmitter function that is stored in presynaptic vesicles by the action of vesicular glutamate transporters (VGLUTs) and under physiological conditions is found at a concentration of 100 mmol/L per vesicle. Different mechanisms are involved in the release of glutamate (reviewed in Meldrum, 2000). Glutamate is mainly released from the vesicles in a Ca2+-dependent mechanism that involves N- and P/Q-type voltage-dependent Ca2+ channels, closely linked to vesicle docking sites. However, glutamate can also be released by reverse operation during reduction of Na+ and K+ gradient across the membrane like for example during cerebral ischemia. Interestingly, the synaptic release of glutamate is controlled by a wide range of presynaptic receptors that are not only glutamatergic like Group II and Group III of glutamate metabotropic receptors but also cholinergic such as nicotinic and muscarinic, adenosine (A1), kappa opioid, γ-aminobutyric acid (GABA)B, cholecystokinin and neuropeptide Y (Y2) receptors.

The synaptic effects of glutamate are rapidly terminated by action of glutamate transporters (excitatory amino acid transporters [EAATs]) located on the plasma membrane of astrocytes and neurons. Therefore, pre-synaptically released glutamate is mostly transported via EAATs to astrocytes and only a small portion is re-uptaken from the synaptic cleft into the presynaptic terminals(Rundfeldt et al., 1994; Blanke and VanDongen, 2009).

Following its release, glutamate exerts its effects via ionotropic and metabotropic receptors. Although glutamate is available for binding to receptors for a short time, NMDA receptors show high affinity for this specific neurotransmitter that causes their activation compared to other receptors.

Biological compartments: Glutamate is the most abundant amino acid in the diet, consequently is found at higher levels in plasma compared to cerebrospinal fluid. The blood brain barrier prevents the entry of glutamate, meaning that the glutamate present in CNS is derived from de novo synthesis of this neurotransmitter relying on the recycling of the main resources. Glutamine and α-ketoglutarate are the major precursors of glutamate. Glutamine is converted via phosphate-activated glutaminase to glutamate and ammonia, whereas α-ketoglutarate is transaminated into glutamate (Platt, 2007). In glial cells, the glutamate is metabolised via glutamine synthase into glutamine or metabolised into α-ketoglutarate. These products are actively transported out of the glial cells and back into the pre-synaptic terminals for subsequent re-synthesis and storage of glutamate.

Five transporters of glutamate have been identified in the CNS. Two are expressed predominantly in glia and three in neurons (reviewed in Meldrum, 2000). The presence of glutamate has also been demonstrated in other tissues and organs as glutamate receptors have been found to be expressed in pancreatic β-cells, osteoblasts and osteoclasts of bones (Nedergaard et al., 2002).

General role in biology: In mature nervous system, glutamate is known to play important role in synaptic plasticity. Similarly important is this neurotransmitter during development where it regulates neurogenesis, neurite outgrowth, synaptogenesis and apoptosis (reviewed in Mattson, 1996; Meldrum, 2000; Mattson, 2008).

The proper functioning of the central nervous system relays on the physiological homeostasis between glutamate and GABA, creating the opposite excitatory/inhibitory forces in the brain. Together, these two neurotransmitters constitute more than 90% of all neurotransmission. If this homeostasis is disturbed it could lead to anxiety disorders (Wieronska et al., 2015).

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). ?

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

No OECD methods are available to measure glutamate release.

There are radioactive assays like [3H]glutamate release assay and spectrophotometric commercially available kits to measure glutamate in cell culture medium (release) or intracellular (cell lysate) using LC-MS. Furthermore, neurotransmitters including glutamate can be measured by HPLC with fluorescence detector.

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

Whereas glutamatergic transmission in vertebrates is excitatory, mediated by glutamate-gated cation channels, glutamate serves as both an excitatory and an inhibitory transmitter in invertebrates (Cleland, 1996).

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

Blanke ML, VanDongen AMJ. (2009) Activation Mechanisms of the NMDA Receptor. In: Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press; Chapter 13. Available from: http://www.ncbi.nlm.nih.gov/books/NBK5274/

Cleland TA. (1996) Inhibitory glutamate receptor channels. Mol Neurobiol. 13: 97-136.

Mattson MP. (1996) Calcium and free radicals: mediators of neurotrophic factor and excitatory transmitter regulated developmental plasticity and cell death. Perspect Dev Neurobiol. 3: 79-91.

Mattson MP. (2008) Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci. 1144: 97-112.

Meldrum BS. (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr. 130: 1007S-1015S.

Nedergaard M, Takano T, Hansen AJ. (2002) Beyond the role of glutamate as a neurotransmitter. Nat Rev Neurosci. 3: 748-755.

Platt SR. (2007) The role of glutamate in central nervous system health and disease-a review. Vet J. 173: 278-286.

Rundfeldt C, Wlaź P, Löscher W. (1994) Anticonvulsant activity of antagonists and partial agonists for the NMDAR-associated glycine site in the kindling model of epilepsy. Brain Res. 653: 125-130.

Wieronska JM, Kłeczek N, Woźniak M, Gruca P, Łasoń-Tyburkiewicz M, Papp M, Brański P, Burnat G, Pilc A. (2015) mGlu₅-GABAB interplay in animal models of positive, negative and cognitive symptoms of schizophrenia.Neurochem Int. 88: 97-109.