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Relationship: 630

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, A paroxysmal depolarizing shift leads to Occurrence, Epileptic 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
Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain adjacent High Moderate Ping Gong (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 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
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Dichter and Ayala (1987) reviewed our current understanding of the simple focal seizure models, where interictal discharge (ID) and seizures seem most closely related. In acute focal epilepsy, during the ID, thousands of neurons in the focus synchronously undergo an unusually large depolarization (the paroxysmal depolarizing shift or PDS), superimposed on which is a burst of action potentials. The PDS is followed by a hyperpolarizing potential (the post-PDS HP) and neuronal inhibition. In areas surrounding the focus, many neurons are inhibited during the ID. In distant projection areas, neurons can be excited briefly but more often are inhibited during the ID, according to their synaptic interactions. Axons that end within the focus generate action potentials, which can "backfire" and propagate antidromically. In addition, during the ID, at the site of the focus, extracellular levels of K+ increase and levels of Ca2+ decrease, presumably because of exit of K+ from and entry of Ca2+ into neuronal processes during the intense neuronal activity.

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 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

As reviewed by Dichter and Ayala (1987), when seizures develop, at least in the acute focus, the neurons show a characteristic sequence of events: the post-PDS HP becomes smaller, gradually disappears, and is replaced by a depolarization, on top of which are smaller depolarizing waves that resemble small PDSs. This series of events occurs synchronously in the population of neurons within the focus, and the EEG develops after discharges (ADs) after several successive IDs. The ADs become longer with each ID and then progress into a seizure. Meanwhile, near and distant areas of brain are brought into the seizure process, and the abnormal activity spreads. During this process, levels of extracellular K+ continue to increase until they reach a steady-state level well above normal, and levels of extracellular Ca2+ continue to decrease. Finally the seizure subsides, and the neuronal membrane hyperpolarizes well beyond control level. It is not known whether this orderly progression from IDs to seizures occurs in the same way in chronic epileptic foci or in many forms of human epilepsy.

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

A crucial issue related to the development of the ID is how so many neurons within a focus develop simultaneous depolarizations. Synchronization may occur by any of several synaptic and nonsynaptic mechanisms: (i) recurrent synaptic excitation, (ii) antidromic activation of the afferent fibers, (iii) ephaptic interactions due to large currents that flow through extracellular spaces, (iv) changes in extracellular ionic concentrations, (v) electrical coupling between cortical neurons, and (vi) the diffuse liberation of modulators (Dichter and Ayala 1987). Two alternative hypotheses emerged, that could broadly be categorized as the epileptic neuron versus the epileptic network. In practice it really is impossible to divorce the two: epilepsy is essentially a collective phenomenon that requires synchrony amongst large numbers of neurons, but the reason for the excessive synchrony and excitation can be abnormal intrinsic properties (the epileptic neuron), or abnormal circuitry (the epileptic network), or both (in most cases) (Jefferys 2010).

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
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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
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Domain of Applicability

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Most lines of supporting evidence come from studies using human and rodent epilepsy models. See Dichter and Ayala (1987) and Jefferys (2010) for examples.

References

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

Dichter MA, Ayala GF. 1987. Cellular mechanisms of epilepsy: A status report. Science 237: 157-164.

Jefferys JGR. 2010. Advances in understanding basic mechanisms of epilepsy and seizures. Seizure 19:638–46.