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Relationship: 684

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

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
Generation, Amplified excitatory postsynaptic potential (EPSP)
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Occurrence, A paroxysmal depolarizing shift

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 Cataia Ives (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 Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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

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.