GABAergic neurons and GABA(A)-receptors in temporal lobe epilepsy

Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of epilepsy , characterized by recurrent complex partial seizures and hippocampal scler osis. The pathophysiology underlying this disorder remains unidentified. Wh ile a loss of benzodiazepine binding sites is a key diagnostic feature of M TLE, experimental studies have shown enhanced inhibitory transmission and i ncreased expression of GABAA-receptors, suggesting that compensatory mechan isms are operative in epileptic hippocampus. In the present study, changes in the expression and cellular distribution of major GABAA-receptor subunit s were investigated in the hippocampus of pilocarpine-treated rats during t he phase of spontaneous recurrent seizures. A uniform decrease in GABA(A)-r eceptor subunit-immunoreactivity was observed in regions of extensive neuro nal death (i.e. CA1, CA3, hilus), whereas a prominent increase occurred in the dentate gyrus (DG). Most strikingly, the increase was largest for the a lpha 3- and alpha 5-subunits, which are expressed at very low levels in the DG of control rats, suggesting the formation of novel GABA(A)-receptor sub types in epileptic tissue. Furthermore, an extensive loss of interneurons e xpressing the ctl-subunit, representing presumptive basket cells, was seen in the DG. These changes were very similar to those reported in a novel mou se model of MTLE, based on the unilateral injection of kainic acid into the dorsal hippocampus (Bouilleret et al., 1999). This indicates that the regu lation of GABAA-receptor expression is related to chronic recurrent seizure s, and is not due to the extrahippocampal neuronal damage affecting pilocar pine-treated rats. These results allow causal relationships in the inductio n and maintenance of chronic recurrent seizures to be distinguished. The lo ss of a critical number of interneurons in the DG is a possible cause of se izure initiation, whereas the long-lasting upregulation of GABAA-receptors in granule cells represents a compensatory response to seizure activity. (C ) 1999 Elsevier Science Ltd. All rights reserved.