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Objective We determined the role of the neurosteroid-sensitive δ subunit-containing γ-aminobutyric acid A receptors (δ- 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 δ, α4, and γ2 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 patch-clamp technique. Finally, the effects of inhibiting N-methyl- d-aspartate receptors (NMDARs) during SE on the long-term plasticity of δ- 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 δ- GABARs occurred prior to the onset of epilepsy, whereas an increased expression of the γ2- GABAR subunits occurred after seizure onset. MK801 blockade of NMDARs during SE preserved the expression of neurosteroid-sensitive δ- GABARs. NMDAR blockade during SE also prevented the onset of spontaneous seizures. Significance Changes in neurosteroid-sensitive δ- GABAR expression correlated temporally with epileptogenesis. These findings raise the possibility that δ- GABAR plasticity may play a role in epileptogenesis. [ABSTRACT FROM AUTHOR]

Epilepsies consist of a spectrum of neurologic disorders typically characterized by unpredictable and dysfunctional network behaviors in the central nervous system (CNS), which lead to discrete episodes of large bouts of uncontrolled neuronal synchrony that interfere with the normal functioning of the brain. Temporal lobe epilepsy (TLE) is accompanied by changes in interneuronal innervation and modifications in different γ-aminobutyric acid (GABA)A receptor subunits. Hormones play an important role in modulating the overall excitability of neurons, and at the same time hormonal pathways are frequently modified during epilepsy. This review focuses on TLE-correlated modifications of GABAergic transmission, and in particular on the implications of some of our own findings related to GABAARs containing the δ subunits (δ-GABAARs). These are extra- or perisynaptic GABAARs that mediate tonic inhibition, a major component of the inhibitory mechanism in the brain. The most potent endogenous modulators of δ-GABAARs are neurosteroids, which act as positive allosteric modulators. Plasticity of δ-GABAARs during TLE consists of down-regulation of the subunit in the dentate gyrus granule cells (DGGCs), while being up-regulated in interneurons. Surprisingly, the level of tonic inhibition in DGGCs remains unchanged, consistent with the idea that it becomes mediated by GABAARs containing other subunits. In parallel, tonic inhibition in a TLE model ceases to be sensitive to neurosteroid potentiation. In contrast, as predicted by the anatomic plasticity, interneuronal tonic current is increased, and remains sensitive to neurosteroids. These findings have important pharmacologic implications. Where neurosteroids normally have sedative and anticonvulsant effects, bimodal and cell-type specific modulations in their natural targets might weaken the inhibitory control on the dentate gate, under circumstances of altered neurosteroids levels (stress, ovarian cycle, or the postpartum period). [ABSTRACT FROM AUTHOR]

We showed previously that electrographic seizures involving dentate granule cells in organotypic hippocampal slice cultures were dramatically reduced following chronic treatment with the NR2B-selective antagonist, Ro25,6981, but were increased following chronic treatment with the high-affinity competitive antagonist, D(-)-2-amino-5-phosphonopentanoic acid (D-APV). To begin to investigate the potential mechanisms underlying the differential effects of N-methyl-d-aspartate receptor (NMDAR) antagonists on seizures, electrophysiologic experiments were conducted in dentate granule cells in hippocampal slice cultures treated for the entire 17–21 day culture period with vehicle, Ro25,6981 or D-APV. Initial experiments revealed a lack of an association between miniature excitatory postsynaptic current (mEPSC) measures and seizures suggesting that shifts in mEPSC were unlikely to account for the differential effects of D-APV and Ro25,6981 on seizures. However, the amplitude of tonic NMDAR-mediated currents was reduced in cultures treated chronically with D-APV and dramatically enhanced in cultures treated chronically with Ro25,6981. Because tonic NMDAR currents are mediated primarily by extrasynaptic NMDAR, these data show an inverse relationship between changes in extrasynaptic NMDAR function and alterations in seizure expression. [ABSTRACT FROM AUTHOR]