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Relationship: 1859

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased, glutamate leads to Overactivation, NMDARs

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased, glutamate

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Overactivation, NMDARs

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Acetylcholinesterase Inhibition Leading to Neurodegeneration	adjacent	Moderate	High	Allie Always (send email)	Under development: Not open for comment. Do not cite

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI
human	Homo sapiens	Low	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

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

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Glutamate is the main excitatory neurotransmitter in the brain and spinal cord, where it activates both ionotropic and metabotropic receptors (Kandel et al., 2013). N-methyl-D-aspartate (NMDA) receptors are one class of ionotropic glutamate receptors found in the brain. They are unique in that they require multiple ligands, both glutamate and glycine, to first bind before they can open. Under normal conditions, the extracellular concentration of glycine is high enough to allow effective opening of NMDA receptors by glutamate (Kandel et al., 2013). NMDA receptors are also voltage-gated by a magnesium block and requires depolarization of the neuron to which the NMDA receptors are bound before ions can flow through the receptor channel (Kandel et al., 2013). A variety of pathological conditions involve the overactivation of glutamate receptors and result in some form of injury (Lipton and Rosenberg, 1994). For example, elevated extracellular glutamate levels have been shown to occur during periods of seizure activity (Lallement et al., 1991). Excess extracellular glutamate is known to be toxic to neurons and can result in cell death due to calcium dysregulation mediated through NMDA receptor activation (Michaels and Rothman, 1990).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence was collected in multiple ways: literature searches of external databases, review of related KEs and KERS in the AOPWiki, and consultation with experts. Extensive literature searches were conducted in Scopus, Pubmed, and Google Scholar using keywords applicable to each KE, with an initial focus on zebrafish data to then focusing on rat data. Related KEs and KERs in the AOPWiki were also reviewed for relevant evidence and their sources. The “snowball method” was used to find additional articles, i.e., relevant citations within an article were obtained if they provided additional evidence. EndNote reference managing software was used to store results from the literature searches and when possible, a pdf of the manuscript was attached to each record. Papers were reviewed and categorized by whether they contained data to support one or more parts of the AOP. An Excel spreadsheet was used to record reviewed papers and any information worth noting.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Glutamate release into the synaptic cleft is primarily caused by excitatory glutamatergic neurons, however there is evidence showing astrocytes releasing glutamate through a calcium-dependent process. A mechanism explaining how astrocytes release glutamate is not well defined, but it could be released through exocytosis (Nedergaard et al. 2002). Excessive extracellular glutamate overactivates NMDARs and propagates the excitotoxicity caused by some nerve agents (McDonough and Shih, 1997).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Pretreatment with NMDA receptor antagonist MK-801 delayed cell injury and death induced by glutamate toxicity (Michaels and Rothman, 1990).

A rat study by Smolders et al. (1997) demonstrated that seizures initiated by pilocarpine were further mediated through NMDA receptors and that these seizures were terminated upon administration of MK-801, an NMDA receptor antagonist.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

There are no known uncertainties or inconsistencies with this relationship.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Table 1: Summary of available quantitative data describing responses of NMDAR activation by glutamate. Glu = Glutamate. Gly = Glycine.

Upstream Glutamate Release	Downstream NMDA Receptor Activation	Brief Summary	Species / Model	Reference
Upstream Glutamate Release	Downstream NMDA Receptor Activation	Brief Summary	Species / Model	Reference
Glutamate (kinetic model)	Receptor binding kinetics (Summarized in Table 1 of Lester et al., 1993)	Provided a kinetic model of NMDA receptor activation without the assumption of saturating glycine concentrations and provided relevant binding kinetic data for Glu and Gly.	Cultured rat hippocampal neurons	Lester et al. (1993)
Glutamate (kinetic model)	Receptor binding kinetics	Measured the electrophysiological response of neurons to NMDA receptor activation by glutamate, created a best-fitting reaction scheme, and provided the binding rate constants between Glu and NMDA receptors given a saturating concentration of Gly.	Cultured rat hippocampal neurons	Clements and Westbrook (1991)
Glutamate (kinetic model)	Receptor binding kinetics (Summarized in Table 2 of Lester and Jahr, 1992)	Provided a kinetic model of NMDA receptor activation (based on the model of Clements and Westbrook 1991) given a variety of conditions, including Glu and NMDA receptor activation given a saturating concentration of Gly.	Cultured rat hippocampal neurons	{Lester, 1992 #648764@@author-year}
Glutamate (kinetic model)	Receptor activation and binding kinetics (Summarized in Table 2 of Erreger et al., 2005)	Provided a kinetic model which included the individual kinetics of the NR1 and NR2 subunits that compose NMDA receptors with Glu (shown as Scheme 2 in the paper).	HEK293 cells transfected with rat NMDA receptor cDNA \| Xenopus oocytes	Erreger et al. (2005)
N/A	N/A	Developed a computational model of a glutamatergic spine that models intracellular calcium dynamics and sources of calcium influx including activation of NMDA receptors.	Computational model (CA1 pyramidal neuron)	Hu et al. (2018)

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

This relationship has been demonstrated in rats, and human toxicity through this pathway has also been indicated (King and Aaron, 2015).

References

List of the literature that was cited for this KER description. More help

Clements, J. D. & Westbrook, G. L. 1991. Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor. Neuron, 7, 605-13. DOI: 10.1016/0896-6273(91)90373-8.

Erreger, K., Geballe, M. T., Dravid, S. M., Snyder, J. P., Wyllie, D. J. & Traynelis, S. F. 2005. Mechanism of partial agonism at NMDA receptors for a conformationally restricted glutamate analog. J Neurosci, 25, 7858-66. DOI: 10.1523/jneurosci.1613-05.2005.

Hu, E., Mergenthal, A., Bingham, C. S., Song, D., Bouteiller, J. M. & Berger, T. W. 2018. A Glutamatergic Spine Model to Enable Multi-Scale Modeling of Nonlinear Calcium Dynamics. Front Comput Neurosci, 12, 58. DOI: 10.3389/fncom.2018.00058.

Kandel, E., Schwartz, J., Jessell, T., Siegelbaum, S. & Hudspeth, A. J. 2013. Synaptic Integration in the Central Nervous System. Principles of Neural Science, Fifth Edition. Blacklick, United States: McGraw-Hill Publishing.

King, A. M. & Aaron, C. K. 2015. Organophosphate and Carbamate Poisoning. Emergency Medicine Clinics of North America, 33, 133-151. DOI: 10.1016/j.emc.2014.09.010.

Lallement, G., Carpentier, P., Collet, A., Pernot-Marino, I., Baubichon, D. & Blanchet, G. 1991. Effects of soman-induced seizures on different extracellular amino acid levels and on glutamate uptake in rat hippocampus. Brain Research, 563, 234-240. DOI: 10.1016/0006-8993(91)91539-D.

Lester, R. A. & Jahr, C. E. 1992. NMDA channel behavior depends on agonist affinity. J Neurosci, 12, 635-43. DOI: 10.1523/jneurosci.12-02-00635.1992.

Lester, R. A., Tong, G. & Jahr, C. E. 1993. Interactions between the glycine and glutamate binding sites of the NMDA receptor. J Neurosci, 13, 1088-96. DOI: 10.1523/jneurosci.13-03-01088.1993.

Lipton, S. A. & Rosenberg, P. A. 1994. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med, 330, 613-22. DOI: 10.1056/nejm199403033300907.

McDonough, J. H., Jr. & Shih, T. M. 1997. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev, 21, 559-79. DOI: 10.1016/s0149-7634(96)00050-4.

Michaels, R. L. & Rothman, S. M. 1990. Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations. J Neurosci, 10, 283-92. DOI: 10.1523/jneurosci.10-01-00283.1990.

Smolders, I., Khan, G. M., Manil, J., Ebinger, G. & Michotte, Y. 1997. NMDA receptor-mediated pilocarpine-induced seizures: characterization in freely moving rats by microdialysis. Br J Pharmacol, 121, 1171-9. DOI: 10.1038/sj.bjp.0701231.