GABAergic neurons and GABAA-receptors in temporal lobe epilepsy

被引:132
作者
Fritschy, JM [1 ]
Kiener, T
Bouilleret, V
Loup, F
机构
[1] Univ Zurich, Inst Pharmacol, CH-8057 Zurich, Switzerland
[2] Fac Med, INSERM, U 398, F-67085 Strasbourg, France
关键词
D O I
10.1016/S0197-0186(99)00040-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 GABAA-receptors, suggesting that compensatory mechanisms are operative in epileptic hippocampus. In the present study, changes in the expression and cellular distribution of major GABAA-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 alpha 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 subtypes in epileptic tissue. Furthermore, an extensive loss of interneurons expressing the ctl-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 GABAA-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 GABAA-receptors in granule cells represents a compensatory response to seizure activity. (C) 1999 Elsevier Science Ltd. All rights reserved.
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收藏
页码:435 / 445
页数:11
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