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Goddard (1967) was the first to describe that periodic stimulation of neural pathways progressively leads to recurrent behavioural and electrographic seizures. Kindling procedures have provided a substrate for the study of the role of enhanced synaptic efficacy in seizure disorders. It is now considered to be a first choice experimental procedure in the study of the potential mechanisms of epileptogenesis. The phenomenon can be evoked in various brain regions, but amygdala kindling is most frequently used in epilepsy research as a model for complex focal (partial) seizures (Fisher, 1989). Although kindling has been shown to be phenomenologically different from other types of plastic changes in the central nervous system, there are many points of similarity between kindling and the process of long-term potentiation (Sutula et al., 1989).
Kindling has been shown to depend upon functional as well as structural changes in glutamatergic synapses. The anticonvulsant effects of glutamate receptor blocking agents like N-methyl-D-aspartate (NMDA) antagonists seem to be at least partly due to their inhibitory effects on in vitro kindling.
Ictogenesis
Excitability is a key feature of ictogenesis that may originate from individual neurons, neuronal environment or a population of neurons. Excitability arising from single neurons may be caused by alterations in membrane or metabolic properties of individual neurons (Traub et al., 1996). When regulation of environmental, extracellular concentrations of ions or neurotransmitters is suboptimal, the resulting imbalance might enhance neuronal excitation. Collective anatomic or physiologic neuronal alterations may convert neurons into a hyper-excitable neuronal population. In reality, these three theoretical mechanisms are thought to interact during specific ictal episodes. Each epileptic focus is unique as the differential contribution of these three concepts leading to ictal events is thought to differ from focus to focus.
Excitability arising from individual neurons
Functional and perhaps structural changes occur in the postsynaptic membrane, thus altering the character of receptor protein-conductance channels, thereby favouring development of paroxysmal depolarizing shifts (PDS) and enhanced excitability. Epileptic neurons appear to have increased Ca2+ conductance. It may be that latent Ca2+ channels are used, that the efficacy of Ca2+ channels is increased or that the number of Ca2+ channels is chronically elevated. However, development of burst activity depends on the net inward current and not on the absolute magnitude of the inward current. When extracellular K+ concentrations are increased (as during seizure activity), the K+ equilibrium across the neuronal membrane is reduced, resulting in reduced outward K+ currents. The net current will become inward, depolarizing the neuron to the extent that Ca2+ currents will be triggered. This results in a PDS and a burst of spikes (Dichter and Ayala, 1987).
Excitability arising from neuronal microenvironment
Both functional and structural alterations occur in epileptic foci. The functional changes involve concentrations of cations and anions, metabolic alterations, and changes in neuro-transmitter levels. The structural changes involve both neurons and glia. Excessive extracellular K+ depolarizes neurons and leads to spike discharge. During seizures, changes in extracellular Ca2+ (a decrease of 85%) precede those of K+ by milliseconds and Ca2+ levels return to normal more quickly than K+. Glia are able to clear neurotransmitters from the extracellular space and to buffer K+, thus correcting the increased extracellular K+ concentrations that occur during seizures. Epileptic foci may show proliferation of glia that differ however in morphological and physiological properties (Bordey and Sontheimer, 1998). Gliosis will affect glial K+ buffering capacity and hence may contribute to seizure generation.
The epileptic cell population
Collective anatomic or physiologic neuronal alterations might produce progressive, network-dependent facilitation of excitability, perhaps coupled with a decrease of inhibitory influences, e.g. due to selective loss of inhibitory neurons. Mossy fibre sprouting (MFS) is an example of neuronal alterations leading to increased excitability (Cavazos et al., 1991). MFS was demonstrated in patients with refractory temporal lobe epilepsy with hippocampal sclerosis on neuroimaging as well as in numerous animal models of temporal lobe epilepsy (Sutula et al., 1988, 1989). In normal conditions, the dentate granule cells limit seizure propagation through the hippocampal network. However, the formation of recurrent excitatory synapses between dentate granule cells, as is thought to occur after MFS, may transform the dentate granule cells into an epileptogenic population of neurons (McNamara, 1999). Possibly, a vicious cycle develops: seizures cause neuronal death, which results in MFS, which in turn increases seizure frequency.
Mechanisms of Interictal–Ictal Transition
Mechanisms producing signal amplification, synchronicity and spread of activity are likely to be involved in interictal–ictal transitions. In vivo, interictal–ictal transition can seldom be attributed to one theoretical mechanism, but often results from the interaction of different mechanisms.
Nonsynaptic mechanisms
Alterations in ionic microenvironment
Repetitive ictal and interictal activity causes increases in extracellular K+ leading to increased neuronal excitability (Moody et al., 1974). Some neurons are very sensitive to changes in membrane K+ currents, e.g. pyramidal cells in the CA1 region of the hippo-campus (Rutecki et al., 1985).
Active ion transport
Activation of the Na+–K+ pump is important for regulation of neuronal excitability during excessive neuronal discharges. Substances like ouabain that block the Na+–K+ pump can induce epileptogenesis in animal models. Hypoxia or ischaemia can result in Na+–K+ pump failure thus promoting interictal–ictal transition. A Cl−–K+ co-transport mechanism controls the intracellular Cl− concentration and the Cl− gradient across the cell membrane, which regulates effectiveness of GABA-activated inhibitory Cl− currents. Interference with this process could cause a progressive decrease in the effectiveness of GABA-ergic inhibition leading to increased excitability (Engelborghs et al., 2000).
Presynaptic terminal bursting
The amount of transmitter released is related to depolarization of presynaptic terminals. Changes in axon terminal excitability will have effects on synaptic excitation (Engelborghs et al., 2000). Abnormal bursts of action potentials occur in the axonal arborizations of thalamocortical relay cells during epileptogenesis. Since one thalamocortical relay cell ends on a large number of cortical neurons, synchronization can occur, which might play an important role in interictal–ictal transition (Engelborghs et al., 1998a).
Ephaptic interaction
Ephaptic interactions are produced when currents from activated neurons excite adjacent neurons in the absence of synaptic connections. Ephaptic effects are strongly dependent on the size of the extracellular space. When extracellular space is small, ephaptic interactions are promoted (Traub et al., 1985).
Synaptic mechanisms
Two theoretical mechanisms can occur: decreased effectiveness of inhibitory synaptic mechanisms or facilitation of excitatory synaptic events. Both mechanisms will be discussed below.
Neurochemical Mechanisms Underlying Epilepsy
GABA
The GABA hypothesis