Glutamate, GABA and epilepsy

The nature and value of various animal models of epilepsy for the study and understanding of the human epilepsies are reviewed, with special reference to the ILAE classification of seizures. Kindling as a model of complex-partial seizures with secondary generalisation is treated in detail, dwelling principally on the evidence that the neurotransmitters glutamate and GABA are centrally involved in the kindling process. Kindling in the entorhinal cortex-hippocampus system and its relationship to LTP are analysed in detail. Changes in amino acid content in animal and human brain tissue following onset of the epileptic state are reviewed with special reference to glutamate and GABA. Studies of changes in the extent of basal and stimulus-evoked release of glutamate and GABA both in vivo (microdialysis) and in vitro (brain slices) are evaluated. This includes both kindling and other models of epilepsy, and microdialysis of human patients with epilepsy. Experiments which study the influence of pre-synaptic metabotropic glutamate receptors on glutamate release, and consequently on the extent of electrical kindling, are described. This pre-synaptic control of glutamate release can be studied using synaptosomes. The significance of the ability of focal intracerebrally injected glutamate and NMDA to cause (chemical) kindling and the strong sensitivity of this process to pre-treatment with NMDA receptor antagonists is analysed. Electrical and chemical kindling effects are additive, indicating the existence of mechanisms in common. They are both sensitive to NMDA antagonists and the common mechanism is probably NMDA receptor activation due to the presence of exogenous (chemical) or endogenous (electrically-released) extracellular glutamate. The participation of the NMDA receptor in the generation of the spontaneous hyperactivity which characterises the chronic epileptic state is reviewed. This includes the entry of Ca2+ to stimulate various post-synaptic phosphorylation processes, and possible modulation of NMDA receptor population size and sensitivity. The question of whether neurotransmitter glutamate is involved in initiation and/or spread of seizures is discussed.