Plasticity of GABA receptors relevant to neurosteroid actions

A variety of GABA receptor (GABAR) alterations have been described in human temporal lobe epilepsies (TLE) and in animal models of the disease. As tonically and phasically activated GABARs are distinct in their localization, physiological and pharmacological properties, and their function, it is important to distinguish between their alterations in TLE. This report summarizes our findings about the loss of δ-subunit containing GABARs (δ-GABARs) in granule cells of the dentate gyrus and its upregulation in molecular layer interneurons. In dentate gyrus granule cells, the tonic GABA conductance is mediated primarily by δ-GABARs and to a small extent by α5-subunit containing GABARs (α5-GABARs). Therefore, it was somewhat surprising to observe that following the loss of δ-GABARs from the dentate granule cells in the pilocarpine model of TLE in mice, the tonic GABA conductance was still present in these cells. However, pharmacological experiments with specific modulators of δ-GABARs have shown that the preserved tonic conductance is no longer mediated by δ-GABARs. In contrast to granule cells, inhibitory interneurons of the molecular layer had not lost their δ-GABARs, in fact it appeared that the levels of this subunit were upregulated in the latter neurons. Therefore, the tonic GABA conductance in these TLE-affected cells was also larger than that recorded in control molecular layer interneurons. Shifting the weight of δ-GABARs from principal cells to interneurons of the dentate gyrus in a mouse model of TLE implies that the dentate gate will have an entirely different pharmacological profile in TLE. Since δ-GABARs are quite sensitive to neurosteroids and ethanol, exposure of the dentate to these compounds in TLE will enhance excitability by dampening the function of interneurons and leaving the excitability of the granule cells untouched. The reduced interneuronal function in response to neurosteroids or ethanol in TLE may promote propagation of synchronous high frequency discharges through the dentate gyrus, and may lead to a further erosion of the dentate gate when these substances are present (e.g., stress, changes in the ovarian cycle, alcohol consumption).