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Relationship: 1889

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

Activation, Muscarinic Acetylcholine Receptors leads to Occurrence, Focal Seizure

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 Do not cite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
mouse Mus musculus High NCBI
rat Rattus norvegicus High 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

Muscarinic receptors are metabotropic, affecting a target enzyme which typically sends secondary messenger signals (Kandel et al., 2013). Pharmacological evidence indicates the mAChR M1 subtype modulates the M current in sympathetic ganglion neurons. In mice, M1 agonists suppress the M current and results in membrane depolarization that leads to focal seizures (Hamilton et al., 1997). Seizures occurring through the M1 muscarinic receptor have been observed to start at 5-15 minutes after exposure in rats and guinea pigs (Miller, 2015, Sparenborg et al., 1992).

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

M1 Muscarinic receptors are modulators of M-current potassium channel activity (Marrion, 1997). Blocking the M-current through the M1 receptor contributes to cell depolarization, which then leads to the start of epileptiform activity (Greget et al., 2016). The use of muscarinic agonists is well established and often used in animal models of epilepsy and include compounds such as pilocarpine and carbachol (Curia et al., 2008, Turski et al., 1983). It has been suggested that seizures initiated through M1 receptor activation occur when the ratio between glutamatergic and GABAergic activity reaches a threshold (Miller, 2015).

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

Experiments blocking the M2 subtype have not led to a decrease in seizures from acetylcholinesterase inhibitors, only the antagonist for M1 subtype decreased seizure activity (Cruickshank et al., 1994). This demonstrates that the M1 subtype is vital for muscarinic receptor caused seizures. Many studies have noted that delaying administration of M1 antagonist, even for just a short amount of time after exposure, does not halt status epilepticus development (Miller, 2015). This indicates that M1 receptors are not responsible for maintaining seizure activity, they are only responsible for the initial phase (Hamilton et al., 1997). The secondary generalization of the focal seizure is continued by some other mechanism.

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
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

M1 activation leading to focal seizure activity appears in many different species, both genders, and at various life stages. Specific experiments are listed under the empirical evidence above.

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.

Cruickshank, J. W., Brudzynski, S. M. & McLachlan, R. S. 1994. Involvement of M1 muscarinic receptors in the initiation of cholinergically induced epileptic seizures in the rat brain. Brain Research, 643, 125-129. DOI: 10.1016/0006-8993(94)90017-5.

Curia, G., Longo, D., Biagini, G., Jones, R. S. & Avoli, M. 2008. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods, 172, 143-57. DOI: 10.1016/j.jneumeth.2008.04.019.

Davis, W. M. & Hatoum, N. S. 1980. Synergism of the toxicity of physostigmine and neostigmine by lithium or by a reserpine-like agent (Ro4-1284). Toxicology, 17, 1-7. DOI: 10.1016/0300-483x(80)90021-9.

Greget, R., Dadak, S., Barbier, L., Lauga, F., Linossier-Pierre, S., Pernot, F., Legendre, A., Ambert, N., Bouteiller, J. M., Dorandeu, F., Bischoff, S., Baudry, M., Fagni, L. & Moussaoui, S. 2016. Modeling and simulation of organophosphate-induced neurotoxicity: Prediction and validation by experimental studies. NeuroToxicology, 54, 140-152. DOI: 10.1016/j.neuro.2016.04.013.

Hamilton, S. E., Loose, M. D., Qi, M., Levey, A. I., Hille, B., McKnight, G. S., Idzerda, R. L. & Nathanson, N. M. 1997. Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice. Proceedings of the National Academy of Sciences, 94, 13311-13316. DOI: 10.1073/pnas.94.24.13311.

Harrison, P. K., Sheridan, R. D., Green, A. C., Scott, I. R. & Tattersall, J. E. H. 2004. A guinea pig hippocampal slice model of organophosphate-induced seizure activity. Journal of Pharmacology and Experimental Therapeutics, 310, 678-686. DOI: 10.1124/jpet.104.065433.

Kandel, E., Schwartz, J., Jessell, T., Siegelbaum, S. & Hudspeth, A. J. 2013. Modulation of Synaptic Transmission: Second Messengers. Principles of Neural Science, Fifth Edition. Blacklick, United States: McGraw-Hill Publishing.

Marrion, N. V. 1997. Control of M-current. Annu Rev Physiol, 59, 483-504. DOI: 10.1146/annurev.physiol.59.1.483.

Mergenthal, A., Bouteiller, J.-M. C., Yu, G. J. & Berger, T. W. 2020. A Computational Model of the Cholinergic Modulation of CA1 Pyramidal Cell Activity. Frontiers in Computational Neuroscience, 14. DOI: 10.3389/fncom.2020.00075.

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.

Reddy, D. S., Zaayman, M., Kuruba, R. & Wu, X. 2021. Comparative profile of refractory status epilepticus models following exposure of cholinergic agents pilocarpine, DFP, and soman. Neuropharmacology, 191, 108571. DOI: 10.1016/j.neuropharm.2021.108571.

Sparenborg, S., Brennecke, L. H., Jaax, N. K. & Braitman, D. J. 1992. Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman. Neuropharmacology, 31, 357-68. DOI: 10.1016/0028-3908(92)90068-z.

Sykes, D. A., Dowling, M. R. & Charlton, S. J. 2009. Exploring the mechanism of agonist efficacy: A relationship between efficacy and agonist dissociation rate at the muscarinic M3 receptor. Molecular Pharmacology, 76, 543-551. DOI: 10.1124/mol.108.054452.

Tetz, L. M., Rezk, P. E., Ratcliffe, R. H., Gordon, R. K., Steele, K. E. & Nambiar, M. P. 2006. Development of a rat pilocarpine model of seizure/status epilepticus that mimics chemical warfare nerve agent exposure. Toxicol Ind Health, 22, 255-66. DOI: 10.1191/0748233706th268oa.

Turski, W. A., Czuczwar, S. J., Kleinrok, Z. & Turski, L. 1983. Cholinomimetics produce seizures and brain damage in rats. Experientia, 39, 1408-11. DOI: 10.1007/bf01990130.