Estrogen treatment protects GABA(B) inhibition in the dentate gyrus of female rats after kainic acid-induced status epilepticus.

Abstract

We used the paired-pulse inhibition paradigm to determine whether the cell loss in the hilus of the dentate gyrus of female rats after kainic acid (KA)-induced status epilepticus (SE) is associated with functional changes in the dentate gyrus. Additionally, we determined whether the lost function could be preserved by using estrogen neuroprotection. Female rats were ovariectomized and treated either with estrogen replacement (four doses of 2 microg of estradiol every 24 h: two doses before SE, two doses after) or oil. SE was induced by I.P. administration of KA (16 mg/kg) and terminated after 5 h with pentobarbital. After 2 days, hippocampal/dentate gyrus slices were prepared. Population spikes were recorded in the granule cell layer as a response to mixed perforant-path stimulation (10- to 1,000-ms interstimulus intervals). Ratios of the test response to conditioning response were evaluated. Gamma-aminobutyric acid type B (GABAB) receptors were blocked with 400 microM CGP 35348. In slices from oil-treated rats, SE induced a loss of paired-pulse inhibition in the dentate gyrus at the interstimulus intervals marking intermediate facilitation and late depression. There was no such loss of paired-pulse inhibition in estrogen-treated rats. CGP 35348 was unable to alter paired-pulse inhibition in slices form oil-treated rats. In slices from estrogen-treated rats, CGP decreased paired-pulse inhibition at 50-150-ms interstimulus intervals. Comparison of paired-pulse inhibition in slices from oil-treated rats with slices from estrogen-treated rats with CGP 35348 revealed a GABAB-independent difference at interstimulus intervals >300 ms. Our study demonstrated that there is a complete loss of GABAB receptor-mediated inhibition after KA-induced SE in the dentate gyrus. Pretreatment with estrogen can save GABAB-receptor function, probably by neuroprotection of neurons containing the postsynaptic GABAB receptors.