Neurosteroid-sensitive δ-GABAA receptors: A role in epileptogenesis?

Objective: We determined the role of the neurosteroid-sensitive delta subunit-containing gamma-aminobutyric acid A receptors (delta-GABARs) in epileptogenesis. Methods: Status epilepticus (SE) was induced via lithium pilocarpine in adult rats, and seizures were assessed by continuous video-electroencephalography (EEG) monitoring. Finasteride was administered to inhibit neurosteroid synthesis. The total and surface protein expression of hippocampal delta, alpha 4, and gamma 2 GABAR subunits was studied using biotinylation assays and Western blotting. Neurosteroid potentiation of the tonic currents of dentate granule cells (DGCs) was measured by whole-cell patchclamp technique. Finally, the effects of inhibiting N-methyl-D-aspartate receptors (NMDARs) during SE on the long-term plasticity of delta-GABARs, neurosteroid-induced modulation of tonic current, and epileptogenesis were studied. Results: The inhibition of neurosteroid synthesis 4 days after SE triggered acute seizures and accelerated the onset of chronic recurrent spontaneous seizures (epilepsy). The down-regulation of neurosteroid-sensitive delta-GABARs occurred prior to the onset of epilepsy, whereas an increased expression of the gamma 2- GABAR subunits occurred after seizure onset. MK801 blockade of NMDARs during SE preserved the expression of neurosteroid-sensitive delta-GABARs. NMDAR blockade during SE also prevented the onset of spontaneous seizures. Significance: Changes in neurosteroid-sensitive delta-GABAR expression correlated temporally with epileptogenesis. These findings raise the possibility that delta-GABAR plasticity may play a role in epileptogenesis.