This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Event: 383

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. 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. More help

Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.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. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
neuron

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). 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 signaling 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. Further information on Event Components and Biological Context may be viewed on the attached pdf. 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	Anna Price (send email)	Open for citation & comment	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.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

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. 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. 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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). 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. 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.