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Relationship: 1890

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

Occurrence, Focal Seizure leads to Increased, glutamate

Upstream event

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

Occurrence, Focal Seizure

Downstream event

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

Increased, glutamate

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	Low	Karen Watanabe (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 Do not cite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
guinea pig	Cavia porcellus	Moderate	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

The initial focal seizure starts by increasing the firing rate of neurons in a specific area. This is characterized by changes in membrane potential (Turski et al., 1986). Cholinergic nerve agents cause an increase in spontaneous excitatory postsynaptic currents (sEPSC) leading to increased release of glutamate and activation of N-methyl-D-aspartate receptors (NMDARs) (Lallement et al., 1991, Miller, 2015). This response happens quickly after the initial focal seizure and is then sustained for a longer period of time (McDonough and Shih, 1997).

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

Seizure activity has been shown to cause glutamate release (Lallement et al., 1991). Glutamate is the main excitatory transmitter in the brain and spinal cord, where it activates both ionotropic and metabotropic receptors (Kandel et al., 2013).

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 (Glu) 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 (Nedergaard et al., 2002). A mechanism explaining how astrocytes release glutamate is not well defined, but it could be released through exocytosis (Nedergaard et al., 2002). When focal seizures start, the firing of glutamatergic neurons releases glutamate (Lallement et al., 1991). While the change in spiking activity of individual neurons at seizure onset appears to be heterogenous, there is an apparent increase in neuronal firing rate in some populations of neurons (Truccolo et al., 2011).

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

Exposure to nerve agents that induce seizures also increases free glutamate levels. Rats that did not experience seizures also did not have increased free glutamate levels (Lallement et al., 1991)
Experiments on rats have indicated delayed changes in free glutamate levels after seizure onset, indicating that the activity is in response to seizure activity, not initializing it (McDonough and Shih, 1997).

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 is not yet an explanation for the mechanisms behind glutamate release in response to seizure activity. Animals that developed seizure activity in response to sarin (aka GB) versus VX intoxication showed increasing extracellular glutamate and no changes in extracellular glutamate, respectively (O’Donnell et al., 2011).

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

The papers in the table below present electroencephalogram (EEG) data from timepoint 0 onwards through local injection of seizure-inducing compounds. Focal seizures can be seen to occur in EEG where there is activity localized between a set or sets of electrodes while normal activity continues in the remaining electrodes (Britton et al., 2016). Additionally, the full spectrum of the EEG is not published, and one would need to contact the author.

Table 1. Summary of available quantitative data describing changes in glutamate (Glu) due to focal seizure. 4-AP = 4-aminopyridine; ACh = acetylcholine; Ala = alanine; Asp = aspartate; GABA = gamma aminobutyric acid; Gln = glutamine, Gly = glycine, Tau = taurine.

Upstream Focal Seizure	Downstream Glutamate Release	Brief Summary	Species / Model	Reference
Upstream Focal Seizure	Downstream Glutamate Release	Brief Summary	Species / Model	Reference
EEG activity (intracranial)	Extracellular Glu level profile through an electrochemical biosensor based on H₂O₂ production. (Entorhinal cortex)	Induction of seizure activity through administration of 4-AP into the entorhinal cortex.	Adult male Wistar rats (250-300g)	Morales-Villagrán et al. (2008)
EEG activity (ECoG). Seizure severity score over time.	Glutamate diasylate levels measured over time - microdialysis (hippocampus)	Induced seizure activity through intrahippocampal administration of pilocarpine and monitored EEG activity. Additionally measured various neurotransmitter concentrations including Glu and GABA.	Male albino Wistar rats (270-320g)	Meurs et al. (2008)
EEG activity (intracranial)	Glutamate diasylate levels measured over time - microdialysis (hippocampus)	Induced seizure activity through administration of bicuculline, electrical stimulation, or 4-AP, and performed simultaneous EEG recording.	Adult male Wistar rats (250-350g)	Medina-Ceja et al. (2015)
EEG activity (intracranial)	Glutamate diasylate levels measured over time - microdialysis (Hippocampus CA1)	Induction of seizure activity through administration of 4-AP into the hippocampal CA1 region and performed simultaneous microdialysis.	Adult male Wistar rats (200-250g)	Peña and Tapia (1999)
EEG activity (intracranial)	Glutamate diasylate levels measured over time - microdialysis (hippocampus and striatum)	Induced seizure activity through administration of 4-AP, simultaneous microdialysis in either hippocampus or entorhinal cortex, which measured Glu, Gln, Gly, Tau, and Ala	Adult male Wistar rats (240-260g)	Medina-Ceja et al. (2000)
EEG activity (attached to skull surface)	Glutamate diasylate levels measured over time - microdialysis (striatum)	Induced seizure activity with AChE inhibitors sarin (GB) or VX with simultaneous microdialysis in striatum which included neurotransmitters Glu, ACh, Asp, and GABA.	Male Hartley Guinea Pigs (250-350g)	O’Donnell et al. (2011)

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

Britton, J. W., Frey, L. C., Hopp, J. L., Korb, P., Koubeissi, M. Z., Lievens, W. E., Pestana-Knight, E. M. & St. Louis, E. K. 2016. In: ST. LOUIS, E. K. & FREY, L. C. (eds.) Electroencephalography (EEG): An Introductory Text and Atlas of Normal and Abnormal Findings in Adults, Children, and Infants. Chicago: American Epilepsy Society Copyright ©2016 by American Epilepsy Society.

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.

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.

Medina-Ceja, L., Morales-Villagrán, A. & Tapia, R. 2000. Action of 4-aminopyridine on extracellular amino acids in hippocampus and entorhinal cortex: a dual microdialysis and electroencehalographic study in awake rats. Brain Res Bull, 53, 255-62. DOI: 10.1016/s0361-9230(00)00336-1.

Medina-Ceja, L., Pardo-Peña, K., Morales-Villagrán, A., Ortega-Ibarra, J. & López-Pérez, S. 2015. Increase in the extracellular glutamate level during seizures and electrical stimulation determined using a high temporal resolution technique. BMC Neurosci, 16, 11. DOI: 10.1186/s12868-015-0147-5.

Meurs, A., Clinckers, R., Ebinger, G., Michotte, Y. & Smolders, I. 2008. Seizure activity and changes in hippocampal extracellular glutamate, GABA, dopamine and serotonin. Epilepsy Res, 78, 50-9. DOI: 10.1016/j.eplepsyres.2007.10.007.

Miller, S. L. 2015. The Efficacy of LY293558 in Blocking Seizures and Associated Morphological, and Behavioral Alterations Induced by Soman in Immature Male Rats and the Role of the M1 Muscarinic Acetylcholine Receptor in Organophosphate Induced Seizures. Doctor of philosophy in the neuroscience graduate program Doctoral dissertation, Uniformed Services University.

Morales-Villagrán, A., Medina-Ceja, L. & López-Pérez, S. J. 2008. Simultaneous glutamate and EEG activity measurements during seizures in rat hippocampal region with the use of an electrochemical biosensor. J Neurosci Methods, 168, 48-53. DOI: 10.1016/j.jneumeth.2007.09.005.

Nedergaard, M., Takano, T. & Hansen, A. J. 2002. Beyond the role of glutamate as a neurotransmitter. Nature Reviews Neuroscience, 3, 748-755. DOI: 10.1038/nrn916.

O’Donnell, J. C., McDonough, J. H. & Shih, T.-M. 2011. In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of acetylcholine and glutamate. Archives of Toxicology, 85, 1607-1616. DOI: 10.1007/s00204-011-0724-z.

Peña, F. & Tapia, R. 1999. Relationships among seizures, extracellular amino acid changes, and neurodegeneration induced by 4-aminopyridine in rat hippocampus: a microdialysis and electroencephalographic study. J Neurochem, 72, 2006-14. DOI: 10.1046/j.1471-4159.1999.0722006.x.

Truccolo, W., Donoghue, J. A., Hochberg, L. R., Eskandar, E. N., Madsen, J. R., Anderson, W. S., Brown, E. N., Halgren, E. & Cash, S. S. 2011. Single-neuron dynamics in human focal epilepsy. Nat Neurosci, 14, 635-41. DOI: 10.1038/nn.2782.

Turski, L., Cavalheiro, E. A., Sieklucka-Dziuba, M., Ikonomidou-Turski, C., Czuczwar, S. J. & Turski, W. A. 1986. Seizures produced by pilocarpine: neuropathological sequelae and activity of glutamate decarboxylase in the rat forebrain. Brain Res, 398, 37-48. DOI: 10.1016/0006-8993(86)91247-3.