GABAA receptor modulation by neurosteroids in models of temporal lobe epilepsies

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 GABA(A) Rs containing the δ subunits (δ-GABA(A) Rs). These are extra- or perisynaptic GABA(A) Rs that mediate tonic inhibition, a major component of the inhibitory mechanism in the brain. The most potent endogenous modulators of δ-GABA(A) Rs are neurosteroids, which act as positive allosteric modulators. Plasticity of δ-GABA(A) Rs 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 GABA(A) Rs 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).