GABAergic neurons and GABA A-receptors in temporal lobe epilepsy

• Published in: Neurochemistry international Vol. 34; no. 5; pp. 435 - 445
• Main Authors: Fritschy, Jean-Marc, Kiener, Tania, Bouilleret, Viviane, Loup, Fabienne
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.1999
• Subjects: Animals; Dentate Gyrus - chemistry; Dentate Gyrus - metabolism; Dentate Gyrus - pathology; Epilepsy, Temporal Lobe - chemically induced; Epilepsy, Temporal Lobe - metabolism; Epilepsy, Temporal Lobe - pathology; gamma-Aminobutyric Acid - physiology; Hippocampus - chemistry; Hippocampus - metabolism; Hippocampus - pathology; Immunoenzyme Techniques; Interneurons - pathology; Male; Neurons - metabolism; Neurons - pathology; Pilocarpine; Rats; Rats, Wistar; Receptors, GABA-A - analysis; Receptors, GABA-A - metabolism
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/S0197-0186(99)00040-6

Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of epilepsy, characterized by recurrent complex partial seizures and hippocampal sclerosis. The pathophysiology underlying this disorder remains unidentified. While a loss of benzodiazepine binding sites is a key diagnostic feature of MTLE, experimental studies have shown enhanced inhibitory transmission and increased expression of GABA A-receptors, suggesting that compensatory mechanisms are operative in epileptic hippocampus. In the present study, changes in the expression and cellular distribution of major GABA A-receptor subunits were investigated in the hippocampus of pilocarpine-treated rats during the phase of spontaneous recurrent seizures. A uniform decrease in GABA A-receptor subunit-immunoreactivity was observed in regions of extensive neuronal death (i.e. CA1, CA3, hilus), whereas a prominent increase occurred in the dentate gyrus (DG). Most strikingly, the increase was largest for the α3- and α5-subunits, which are expressed at very low levels in the DG of control rats, suggesting the formation of novel GABA A-receptor subtypes in epileptic tissue. Furthermore, an extensive loss of interneurons expressing the α1-subunit, representing presumptive basket cells, was seen in the DG. These changes were very similar to those reported in a novel mouse model of MTLE, based on the unilateral injection of kainic acid into the dorsal hippocampus ( Bouilleret et al., 1999). This indicates that the regulation of GABA A-receptor expression is related to chronic recurrent seizures, and is not due to the extrahippocampal neuronal damage affecting pilocarpine-treated rats. These results allow causal relationships in the induction and maintenance of chronic recurrent seizures to be distinguished. The loss of a critical number of interneurons in the DG is a possible cause of seizure initiation, whereas the long-lasting upregulation of GABA A-receptors in granule cells represents a compensatory response to seizure activity.