Abstracts

RATIONALE: Functional GABA[sub]B[/sub] receptors are composed of heterodimers consisting of two subunits, GABA[sub]B[/sub]R1 and GABA[sub]B[/sub]R2 of which there are several isoforms. Previous studies have reported impaired function of pre- and postsynaptic GABA[sub]B[/sub] receptors in animal models of temporal lobe epilepsy (TLE). It is presently unknown whether epileptogenesis is associated with a change in expression or isoform composition of GABA[sub]B[/sub] receptor subunits.
METHODS: We used the mouse kainate model of TLE, where kainic acid was injected into the left dorsal hippocampus of adult mice (0.04 [mu]g, 40 nl). In this immunohistochemical study, changes in the distribution of GABA[sub]B[/sub]R1a, GABA[sub]B[/sub]R1b, and GABA[sub]B[/sub]R2 proteins were investigated at different time points (1 day, 1 week, 1 month, and 3 months) in hippocampus, dentate gyrus, and entorhinal cortex.
RESULTS: Analysis of GABA[sub]B[/sub] receptor immunoreactivity in control mice revealed a subfield- and layer-specific pattern in the hippocampal formation, with highest levels in CA3 strata oriens and lacunosum moleculare. As early as one day after kainate injection, Nissl staining showed extensive neuronal degeneration in CA1, the portion of CA3 located between the blades of the dentate gyrus, and the dentate hilus. Labeling for all three GABA[sub]B[/sub] receptor subunits was markedly reduced in these regions. In CA1, changes in GABA[sub]B[/sub] receptors were observed mostly in stratum radiatum. At one and three months, GABA[sub]B[/sub]R1a appeared more preserved than GABA[sub]B[/sub]R1b, suggesting a difference in vulnerability between these isoforms. In dentate gyrus, kainate treatment induced pronounced granule cell dispersion and a concomitant increase in GABA[sub]B[/sub] receptor staining in the granule cell layer. In contrast, no changes were observed in the dentate molecular layer for all three subunits. Moreover, acute loss of GABA[sub]B[/sub]R1-immunopositive interneurons occurred after kainate injection, while surviving interneurons were enlarged and intensely stained at one and three months. Finally, the entorhinal cortex exhibited mild gliosis, but no changes in GABA[sub]B[/sub] receptor staining when compared to control mice.
CONCLUSIONS: These results suggest that acute reduction of presumably both pre- and postsynaptic GABA[sub]B[/sub]R1b subunit-containing GABA[sub]B[/sub] receptors and loss of specific subsets of interneurons contribute to epileptogenesis in this model of TLE. Long-term upregulation of GABA[sub]B[/sub] receptors in dentate gyrus may represent a compensatory mechanism in response to seizure activity.
Support: Swiss National Science Foundation 31-063901.00.