Diminished allopregnanolone enhancement of GABA(A) receptor currents in a rat model of chronic temporal lobe epilepsy

1. Neurosteroid modulation of GABAA receptors present on dentate granule ce lls (DGCs) acutely isolated from epileptic (epileptic DGCs) or control rats (control DGCs) was studied by application of GABA with or without the modu lators and by measuring the amplitude of peak whole-cell currents. 2. In epileptic DGCs, GABA efficacy (1394 +/- 277 pA) was greater than in c ontrol DGCs (765 +/- 38 pA). 3. Allopregnanolone enhanced GABA-evoked currents less potently in epilepti c DGCs (EC50 = 92.7 +/- 13.4 nM) than in control DGCs (EC50 = 12.9 +/- 2.3 nM). 4. Pregnenolone sulfate inhibited GABA-evoked currents with similar potency and efficacy in control and epileptic DGCs. 5. Diazepam enhanced GABA-evoked currents less potently in epileptic (EC50 = 69 +/- 14 nM) compared to the control DGCs (EC50 = 29.9 +/- 5.7 nM). 6. There were two different patterns of zolpidem modulation of GABA(A) rece ptor currents in the epileptic DGCs. In one group, zolpidem enhanced GABAA receptor currents but with reduced potency compared to the control DGCs (EC 50 = 134 +/- 20 nM vs. EC50 = 52 +/- 13 nM). In the second group of epilept ic DGCs zolpidem inhibited GABAA receptor currents, an effect not observed in control DGCs. 7. Epileptic DGCs were more sensitive to Zn2+ inhibition of GABA(A) recepto r currents (IC50 = 19 +/- 6 muM) compared to control (IC50 = 94.7 +/- 7.9 m uM). 8. This study demonstrates significant differences between epileptic and co ntrol DGCs. We conclude that (1) diminished sensitivity of GABA(A) receptor s of epileptic DGCs to allopregnanolone can increase susceptibility to seiz ures; (2) reduced sensitivity to diazepam and zolpidem, and increased sensi tivity to Zn2+ indicate that loss of allopregnanolone sensitivity is likely to be due to altered subunit expression of postsynaptic GABA(A) receptors present on epileptic DGCs; and (3) an inverse effect of zolpidem in some ep ileptic DGCs demonstrates the heterogeneity of GABA(A) receptors present on epileptic DGCs.