Upstream eventGeneration, Amplified excitatory postsynaptic potential (EPSP)
Occurrence, A paroxysmal depolarizing shift
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||Moderate||Moderate|
Life Stage Applicability
Key Event Relationship Description
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 Supporting this KER
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).
For the first hypothesis, Higashida and Brown (1986) and Madison et al. (1986) have demonstrated that epilepsy occurs when the usual balance of these normal events is altered by a change in synaptic efficacy or a change in the control of intrinsic membrane currents. The reason that any given form of epilepsy may develop in a given brain region may depend on (i) differences in densities and locations of channels on various neurons, (ii) the interaction of intrinsic currents with one another and with synaptic currents under physiological conditions, (iii) the local synaptic organization of a given area, and (iv) the liberation of endogenous synaptic modulators that may alter the various voltagedependent membrane currents through second messenger pathways.
For the alternative hypothesis, many studies have shown that in epilepsy models, this is most readily accomplished by inhibiting K+ currents and by allowing the slower Ca2+ currents to be expressed (see review by Dichter and Ayala (1987)). Under more "natural" circumstances, a variety of possible mechanisms may contribute to the development of endogenous burst propensity in the absence of exogenous epileptogenic agents: (i) neuromodulators (acetylcholine, norepinephrine, and peptides) can reduce K+ currents (although stimulation of endogenous pathways, even intensely, has not been shown to produce sufficient inhibition of K+ currents to result in burst firing); (ii) both elevation of extracellular K ([K+]) and reduction of extracellular Ca ([Ca2+]) can change membrane characteristics and induce burst firing modes; and (iii) anatomical distortion and redistribution of channels after injury and partial denervation as seen in chronic epileptic foci may induce burst firing.
Uncertainties and Inconsistencies
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 ofsynaptic 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.
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 been established between the two key events.
Are there known modulators of the response-response relationships? Yes. There are many modulators documented (see Dichter and Ayala (1987) for review).
Are there models or extrapolation approaches that help describe those relationships? Several different models have been proposed (see Dichter and Ayala (1987) for review).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
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: http://www.ncbi.nlm.nih.gov/books/NBK2510/.
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.