Upstream eventOccurrence, A paroxysmal depolarizing shift
Occurrence, Epileptic seizure
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain||adjacent||High||Moderate|
Life Stage Applicability
Key Event Relationship Description
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 anntiromically. 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 Supporting this KER
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.
As summarized by Dichter and Ayala (1987), the EEG hallmarks of focal epilepsy both in animal models and in human epilepsy are the ictal, or seizure, discharge and the interictal spike discharge (ID). The EEG spike most often represents an electrophysiological marker for a hyperexcitable area of cortex and arises in or near an area with a high epileptogenic potential. As such, it has been considered the earliest and simplest electrical manifestation of the epileptic process and has been the target of extensive investigations. In some forms of epilepsy, seizure discharges can be seen to originate electrically and anatomically from the site of spike discharges, and the transition between spikes and seizures has been analyzed in these simple models. In other forms of epilepsy, however, the exact relation between spike discharge and the onset and localization of seizure discharges has been more difficult to determine. Depth electroencephalography from humans with focal epilepsy has demonstrated multiple patterns during the transition to seizure, only some of which resemble that seen in acute experimental focal epilepsy. Whether these observations indicate that the mechanisms underlying the transition in chronic human foci are different from those of the simple acute model is not yet clear.
Uncertainties and Inconsistencies
A cricial 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 (in most cases?) both (Jefferys 2010).
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? No quantitative relationship has yet been established between these two key events.
Are there known modulators of the response-response relationships? Yes. For detailed description of known modulators, see Dichter and Ayala (1987).
Are there models or extrapolation approaches that help describe those relationships? Yes. For more information on different models and hypotheses, see Dichter and Ayala (1987) and Jeffreys (2010).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Most lines of supporting evidence come from studies using human and rodent epilepsy models. See Dichter and Ayala (1987) and Jefferys (2010) for examples.
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.