Selective suppression of hippocampal region hyperexcitability related to seizure susceptibility in epileptic El mice by the GABA-transporter inhibitor tiagabine

Abstract

High seizure susceptibility in El mice is associated with disinhibition in the dentate gyrus (DG) and paired-pulse facilitation in the CA3 area in hippocampal slices [Brain Res. 745 (1997) 165; Brain Res. 779 (1998) 324]. A decrease in γ-aminobutyric acid (GABA)-mediated inhibition and an increase in excitatory inputs to the major neurons seem to be the responsible mechanisms, respectively, for these phenomena. In this study, we examined the effects of tiagabine, an inhibitor of GABA transporter, on hyperexcitation in vivo and in slice preparations. Tiagabine (0.3–0.5 mg/kg) suppressed the occurrence of seizures to about 20% of controls with an ED 50 value of about 0.17 mg/kg. In addition, perfusion of hippocampal slices with tiagabine (20 μM) counteracted the paired-pulse facilitation in the CA3 region over the entire range of interpulse intervals ( P<0.05, two-way ANOVA) and reduced the disinhibition in the DG measured at 10 and 20 ms during short interpulse intervals ( P<0.005, paired t-test). The CA1 region in the El mice, as well as in a non-epileptic parental strain of ddY mice did not respond to the drug. However, frequency potentiation of CA3 was enhanced in both strains ( P<0.05, paired t-test). Our results suggest that within the hippocampus the antiepileptic action of tiagabine is selectively suppressive for hyperexcitability of DG and CA3, which are responsible for seizure-susceptibility in El mice.