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 of epilepsy implies that a reduction of GABA-ergic inhibition results in epilepsy whereas an enhancement of GABA-ergic inhibition results in an anti-epileptic effect (Wong and Watkins, 1982; De Deyn and Macdonald, 1990; De Deyn et al., 1990). Inhibitory postsynaptic potentials (IPSPs) gradually decrease in amplitude during repetitive activation of cortical circuits. This phenomenon might be caused by decreases in GABA release from terminals, desensitization of GABA receptors that are coupled to increases in Cl− conductance or alterations in the ionic gradient because of intracellular accumulation of Cl− (Wong and Watkins, 1982). In case of intracellular accumulation of Cl−, passive redistribution is ineffective. Moreover, Cl−–K+ co-transport becomes less effective during seizures as it depends on the K+ gradient. As Cl−–K+ co-transport depends on metabolic processes, its effectiveness may be affected by hypoxia or ischaemia as well. These mechanisms may play a critical role in ictogenesis and interictal–ictal transition. Several studies have shown that GABA is involved in pathophysiology of epilepsy in both animal models and patients suffering from epilepsy. GABA levels and glutamic acid decarboxylase (GAD) activity were shown to be reduced in epileptic foci surgically excised from patients with intractable epilepsy and in CSF of patients with certain types of epilepsy (De Deyn et al., 1990).
A reduction of 3H–GABA binding has been reported in human brain tissue from epileptic patients whereas PET studies demonstrated reduced benzodiazepine receptor binding in human epileptic foci (Savic et al., 1996). The degree of benzodiazepine receptor reduction showed a positive correlation with seizure frequency. The GABA receptor complex is involved in various animal models of epilepsy as well. Low CSF levels of GABA were revealed in dogs with epilepsy (Loscher and Schwartz-Porsche, 1986). Reduced GAD levels were revealed in the substantia nigra of amygdala-kindled rats (Loscher and Schwark, 1985). Significant alterations in GABA and benzodiazepine binding have been shown in the substantia nigra of genetically seizure-prone gerbils (Olsen et al., 1985). Mice with a genetic susceptibility to audiogenic seizures have a lower number of GABA receptors than animals of the same strain that are not seizure prone (Horton et al., 1982). Several endogenous (guanidino compounds) and exogenous (e.g. bicuculline, picrotoxin, penicillin, pilocarpine, pentylenetetrazol) convulsants inhibit GABA-ergic transmission through inhibition of GABA synthesis or through interaction with distinct sites at the postsynaptic GABAA receptor (De Deyn and Macdonald, 1990; D’Hooge et al., 1996). Convulsant agents that block synaptic GABA-mediated inhibition, amplify the dendritic spike-generating mechanism that involves Ca2+ (Dichter and Ayala, 1987; Fisher, 1989). Synaptic inputs are thought to trigger and synchronize this process throughout a population of cells, which then might result in an epileptic seizure. Several AEMs are GABA analogues, block GABA metabolism or facilitate postsynaptic effects of GABA. However, a study evaluating dose-dependent behavioural effects of single doses of vigabatrin in audiogenic sensitive rats, suggests that the anti-epileptic properties of vigabatrin not only depend on GABA-ergic neurotransmission but might also be explained by decreased central nervous system levels of excitatory amino acids or increased glycine concentrations (Engelborghs et al., 1998b).
Glutamate
In rodent models, altering glutamate receptor or glutamate transporter expression by knockout or knockdown procedures can induce or suppress epileptic seizures (Chapman et al., 1996; Kabova et al., 1999; Chapman, 2000). Regardless of the primary cause, synaptically released glutamate acting on ionotropic and metabotropic receptors appears to play a major role in the initiation and spread of seizure activity (Meldrum, 1994; Chapman et al., 1996; Chapman, 2000). Glutamatergic synapses play a critical role in all epileptic phenomena. Activation of both ionotropic and metabotropic postsynaptic glutamate receptors is proconvulsant. Antagonists of N-methyl-D-aspartate (NMDA) receptors are powerful anticonvulsants in many animal models of epilepsy. Several genetic alterations have been shown to be epileptogenic in animal models.
Glutamate receptors
Studies of epileptiform discharges in hippocampal slices show that the characteristic burst discharge, associated with a ‘paroxysmal depolarizing shift’, is dependent on activation of AMPA receptors for its initial components and NMDA receptors for the later elements (Bengzon et al., 1999; Mazarati and Wasterlain, 1999; Meldrum et al., 1999).
AMPA
AMPA receptor antagonists, either competitive or non-competitive, are anticonvulsant in rodent models (Rogawski and Donevan, 1999). Thus, altered function of AMPA receptors could contribute to proconvulsant or anticonvulsant effects (Meldrum et al., 1999). Evidence has accumulated that Ca2+-permeable AMPA receptors may play a role in epileptogenesis and the brain damage occurring during the prolonged seizures (Rogawski and Donevan, 1999). Because Ca2+-permeable AMPA receptors are predominantly expressed in GABA-ergic inter-neurons, it is hypothesized that some forms of epilepsy might be caused by reduced GABA inhibition resulting from Ca2+-permeable AMPA receptor-mediated excitotoxic death of interneurons (Rogawski and Donevan, 1999).
NMDA
NMDA receptor antagonists are potent anticonvulsants in many animal models, suggesting a role for these receptors in epileptogenesis (Patrylo et al., 1999).
