Related Experiment Videos
GABAergic neurons and GABA(A)-receptors in temporal lobe epilepsy
J M Fritschy1, T Kiener, V Bouilleret
1Institute of Pharmacology, University of Zurich, Switzerland. fritschy@pharma.unizh.ch
Abstract:
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 alpha3- and alpha5-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 alpha1-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.
Insights
Mesial temporal lobe epilepsy (MTLE) involves changes in GABA(A)-receptor subunits in the hippocampus. Seizures may be initiated by interneuron loss, with receptor upregulation acting as a compensatory response.
Area of Science:
- Neuroscience
- Epilepsy Research
- Molecular Biology
Background:
- Mesial temporal lobe epilepsy (MTLE) is the most common epilepsy type, characterized by seizures and hippocampal damage.
- The exact causes of MTLE are unknown, but altered GABA(A)-receptor function is implicated.
- Compensatory mechanisms involving GABA(A)-receptors are suggested in epileptic hippocampi.
Purpose of the Study:
- To investigate changes in GABA(A)-receptor subunit expression and distribution in the hippocampus during spontaneous recurrent seizures in a rat model.
- To determine if these changes are linked to chronic seizures or general neuronal damage.
Main Methods:
- Utilized pilocarpine-treated rats to induce epilepsy and spontaneous recurrent seizures.
- Examined GABA(A)-receptor subunit expression and cellular distribution via immunohistochemistry.
- Compared findings with a mouse model of MTLE induced by kainic acid.
Main Results:
- Decreased GABA(A)-receptor subunit expression in areas of neuronal death (CA1, CA3, hilus).
- Increased expression in the dentate gyrus (DG), particularly for alpha3 and alpha5 subunits, suggesting novel receptor subtypes.
- Significant loss of interneurons expressing the alpha1 subunit in the DG.
Conclusions:
- GABA(A)-receptor expression regulation is associated with chronic recurrent seizures, not just general neuronal damage.
- Loss of DG interneurons may initiate seizures.
- Upregulation of GABA(A)-receptors in granule cells is a compensatory response to seizure activity.