Loss of Allopregnanolone Enhancement of GABAA Receptor Currents in Temporal Lobe Epilepsy
Abstract number :
1.171
Submission category :
Year :
2000
Submission ID :
2877
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Zakaria Mtchedlishvili, Edward H Bertram, Jaideep Kapur, Univ of Virginia, Charlottesville, VA.
RATIONALE: There is plasticity of GABAA receptors (GABAAR) in temporal lobe epilepsy (TLE). Neurosteroids are endogenous, allosteric modulators of GABAAR function synthesized by glia from cholesterol or sex steroids. Allopregnanolone is an anticonvulsant and pregnenolone sulfate is a pro-convulsant neurosteroid. Their action on GABAAR in TLE has not been characterized. METHODS: TLE was induced in rats by Lothman's method of continuous hippocampal stimulation. DGC were acutely isolated from epileptic (epileptic cells) and control rats (control cells). The cells were voltage-clamped to 0mV and GABA was co-applied with varying concentrations of allopregnanolone, Pregnanolone sulfate (PS), diazepam and ZnCl2. RESULTS:GABA evoked currents were enhanced 52.33% ? 3.09 (n = 5) by 10 nM allopregnanolone in control cells and 12.3% ? 3.09, (n = 4) in epileptic cells. There was rightward shift of allopregnanolone concentration response curve in epileptic cells (EC50 = 74.4 nM) compared to controls (EC50 = 10.3 nM). PS (10?M) inhibited GABAAR currents equally in control cells (45.8% ? 4 , n = 14) and epileptic animals (36.8% ? 7.18, n= 9). A detailed concentration response analysis in epileptic (n= 14) and control (n = 9)cells found no differences in EC50 (control, 13.1?M, epileptic 17.4?M) or maximal inhibition. Diazepam (100 nM) enhanced GABA-evoked currents in control cells by 54% ? 3.45, (n = 6) and 36.5% ? 2.96, (n = 9) in epileptics. There was rightward shift of diazepam concentration response curve in epileptic cells (EC50 = 183.9 nM) compared to controls (EC50 = 56.8 nM). Preliminary data showed that Zn2+ inhibition of GABAAR currents was increased in epileptic cells compared to controls. CONCLUSIONS: Endogenous anticonvulsant allopregnanolone enhances GABA evoked currents in DGC of epileptic rats poorly compared to controls. In contrast negative modulation by PS remains unchanged. These selective changes in neurosteroid modulation of GABAAR of epileptic DGC may contribute to increased susceptibility to seizures and catamenial variation of seizures. NIH EFA