The hippocampal formation, including the entorhinal cortex, the dentate gyrus, the cornu ammonis and the subiculum, plays a major role in the generation of temporal lobe epilepsy (TLE). Some forms of TLE are pharmacoresistant when treated with presently marketed drugs. These drugs have been found to act through three principal mechanisms. Drugs such as phenytoin and carbamazepine interfere with sodium current inactivation and prevent the generation of high-frequency discharges. Barbiturates, benzodiazepines, and valproic acid, in contrast, interfere with epileptogenesis by augmenting GABAergic neurotransmission (Macdonald and McLean, 1986). Finally, ethosuximide and dimethadione block T-type Ca2+ currents and thereby interfere with synchronising mechanisms in the thalamus involved in generation of primarily generalised non-convulsant seizures (Coulter et al., 1989). None of these agents is absolutely specific: Phenytoin and valproic acid also block some types of transient Ca2+ currents (Yaari et al., 1987;Rogawski and Porter, 1990); carbamazepine augments some potassium currents (Zona et al., 1990) and interferes with adenosine effects in the CNS (Skeritt et al., 1982); and ethosuximide is also a GABA, receptor blocker (Coulter et al., 1990). It is often assumed that the significant non-specificity of these drugs accounts for their effectiveness in very different seizure disorders, for their usefulness in other diseases (e.g., pain attacks and psychotic disorders), as well as for their frequent side effects.
Neuropathological findings have shown that temporal lobe epilepsy is often associated with loss of neurons in the dentate hilus and in the CA1 and CA3 fields, and with a proliferation of astrocytes particularly in CA1 when hippocampal sclerosis develops. However, cell loss and/or reorganization is not confined to the hippocampus. Reductions in cell number may also occur in the entorhinal cortex and in the dentate gyrus (Babb and Brown, 1986). In the latter region, investigators have reported reductions of calbindin both in human tissue and in animal models (Baimbridge and Miller, 1984), as well as changes in other intracellular proteins. Nerve growth factors may be upregulated (Gall and Isackson, 1989), and are perhaps involved in the reorganization indicated by enhanced zinc staining and kainate binding (Gall and Isackson, 1989;Sutula et al., 1988;Represa et al., 1990). These and other alterations may underlie an increased readiness for seizure generation in these hippocampal structures. Which, if any, of