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Relationship: 684


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

Generation, Amplified excitatory postsynaptic potential (EPSP) leads to Occurrence, A paroxysmal depolarizing shift

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 Moderate 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

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

Life Stage Applicability

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

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

Blockage of the ion channel of the iGABAR causes membrane depolarization and a reduction in inhibitory postsynaptic currents. This leads to the increased, abnormal neuron firing that causes a wave of depolarization throughout the brain/neuronal tissue. At the level of single neurons, epileptiform activity consists of sustained neuronal depolarization resulting in a burst of action potentials, a plateau-like depolarization associated with completion of the action potential burst, and then a rapid repolarization followed by hyperpolarization. This sequence is called the paroxysmal depolarizing shift. The bursting activity resulting from the relatively prolonged depolarization of the neuronal membrane is due to influx of extracellular Ca2+, which leads to the opening of voltage-dependent Na+ channels, influx of Na+, and generation of repetitive action potentials. The subsequent hyperpolarizing afterpotential is mediated by iGABA receptors and Cl- influx, or by K+ efflux, depending on the cell type (Bromfield et al 2006).

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

It has been proposed that as the potentiated EPSP begins to depolarize the neuron, a threshold is reached for the development of a slowly inactivating Na+ current that amplifies the depolarization. As depolarization continues, the low threshold Ca2+ current may turn on to further depolarize the neuron, while NMDA-mediated excitatory synapses become more effective. Eventually, both higher threshold Na+ and Ca2+ currents are activated, and the neuron discharges with a burst of action potentials and an additional slow depolarization (Herron et al. 1985; Dingledine et al. 1986). This hypothesis involves the interplay of both synaptic and voltage-dependent intrinsic events that occur in normal central neurons.

An alternative hypothesis for PDS generation focuses more on changes in the intrinsic properties of neurons resulting in the development of burst firing independent of a primary change in synaptic interactions (Dichter and Ayala 1987).

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

In addition to the above two hypotheses with empirical evidence, some investigators have proposed that neurons with endogenous bursting characteristics must act as a pacemaker in order for epileptiform activity to develop (see review by Dichter and Ayala (1987)). Such neurons would be the CA2 and CA3 pyramidal cells in the hippocampus, layer IV and superficial layer V neocortical pyramidal cells, or the abnormally burst-firing neurons in chronic neocortical foci. This hypothesis is supported by the demonstration of the lower threshold for the induction of interictal discharges by epileptogenic agents in CA2 and CA3 and layer IV, the spread of abnormal activity from these areas to nearby areas in some experimental foci, and by the correlation of the number of bursting cells with the seizure frequency in chronic foci.

However, this hypothesis has been challenged on theoretical grounds by models that demonstrate that a system with either positive or negative feedback elements does not require unstable individual elements in order to develop oscillating behavior. There is also experimental evidence against the obligatory involvement of neurons with endogenous burst-firing characteristics. Studies of in vivo hippocampal penicillin epilepsy and in vitro low Ca2+-high K+ models of epilepsy indicate that area CAl is able to develop spontaneous IDs and seizures independent of areas CA2 and CA3. In addition, neocortical and spinal cord cultures, in which individual neurons do not discharge with intrinsic bursts, become organized into small synaptic networks that show synchronized "burst" behavior-all as a result of synaptic interactions. Thus it appears that endogenous, Ca2+-dependent bursts are not strictly necessary for the development of synchronous bursting activity in a neural network, although their presence may be facilitatory and CNS regions containing such burst-firing neurons may have a particularly high epileptiform potential.

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
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

Numerous studies have documented experimental evidence in support of this relationship even though the underlying mechanisms are still not completely understood. See reviews of Bromfield et al. (2006) and Dichter and Ayala (1987) for studies using rat or human tissues or cell lines as the experimental subject.


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

Bromfield EB, Cavazos JE, Sirven JI. 2006. Chapter 1, Basic Mechanisms Underlying Seizures and Epilepsy. In: An Introduction to Epilepsy [Internet]. West Hartford (CT): American Epilepsy Society; Available from:

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

Dingledine R, Hynes MA, King GL. 1986. Involvement of N-methyl-D-aspartate receptors in epileptiform bursting in the rat hippocampal slice. J Physiol. 380:175-89.

Herron CE, Williamson R, Collingridge GL. 1985. A selective N-methyl-D-aspartate antagonist depresses epileptiform activity in rat hippocampal slices. Neurosci Lett. 61(3):255-60.

Higashida H, Brown DA. 1986. Two polyphosphatidylinositide metabolites control two K+ currents in a neuronal cell. Nature. 323(6086):333-5.

Madison DV, Malenka RC, Nicoll RA. 1986. Phorbol esters block a voltage-sensitive chloride current in hippocampal pyramidal cells. Nature. 321(6071):695-7.