Biphasic differential changes of GABA A receptor subunit mRNA levels in dentate gyrus granule cells following recurrent kindling-induced seizures

Abstract

GABA A receptor α1, β3 and γ2 subunit mRNA levels have been measured in hippocampus using in situ hybridization, following 1, 10 and 40 seizures produced by rapid kindling stimulations. Major alterations of gene expression were largely confined to the dentate gyrus. One stimulus-induced seizure reduced γ2 mRNA levels in the dentate gyrus by 30%. In contrast, mRNA expression increased for α1 in CA1 and CA3 and for, β3 in CA1 to arround 30% above control values. Ten stimulations reduced β3 (by 19%) and γ2 (by 37%) mRNA expression in the dentate gyrus. No changes were observed in other hippocampal subregions. Forty kindling-induced seizures led to biphasic alterations of subunit mRNA levels in dentate gyrus with only minor changes in CA1-CA3. Up to 4 h after the last seizure mRNA expression for α1 was slightly decreased in dentate gyrus, whereas marked reductions were observed for β3 and γ2 (by 41% and 48%, respectively). Between 12 and 48 h there were major increases of α1 (by 59%) and γ2 (by 35%) mRNA levels but no significant changes of β3 mRNA expression. Subunit mRNA levels had returned to control values after 5 days, which argues against a direct involvement of GABA A receptor in kindling-evoked hyperexcitability. The rapid and transient, biphasic changes of GABA A receptor subunits following recurrent seizures could play an important role in stabilizing granule cell excitability, thereby reducing seizure susceptibility. The differential regulation of subunit mRNA levels following seizures suggests a novel mechanism for changing the physiological properties of dentate granule cells through possible GABA A receptor complexes with different subunit composition.