ABERRANT EXPRESSION OF GABA(A) RECEPTOR SUBUNITS IN THE TOTTERING MOUSE - AN ANIMAL-MODEL FOR ABSENCE SEIZURES

The single-locus mutant mouse tottering (tg) is an established model f or absence seizures. We have previously reported an impairment in GABA -induced chloride uptake in tg brain [Tehrani and Barnes, Epilepsy Res . 1995;22:13-21]. In order to determine if this alteration in GABA(A) receptor function can be related to specific receptor isoforms, we exa mined the radioligand binding properties of GABA(A) receptors and the expression of GABAA receptor subunit mRNAs in the cerebral cortex. Sat uration binding of [H-3]flunitrazepam revealed a significantly lower K -d value in tg cortical tissues (1.77 +/- 0.05 nM) in comparison to th at for the background C57BL/6J strain (3.23 +/- 0.23 nM), while the B- max values were indistinguishable. Biphasic displacement of [H-3]fluni trazepam binding by 2-oxoquazepam showed that low affinity binding sit es account for 36 +/- 7.6 and 51 +/- 7.5% of the total in control and tg, respectively. The level of [S-35]-t-butylbicyclophosphorothionate (TBPS) binding to tg cortical membranes was 73.6 +/- 5.8% of that in c ontrols. Paired measurements by quantitative reverse transcriptase-pol ymerase chain reaction (RT-PCR) revealed no significant differences in the levels of GABA(A) receptor alpha 1, alpha 3, alpha 5, beta 2, bet a 3, gamma 2 or gamma 3 subunit mRNAs between tg and control cortex. H owever, tg tissues showed elevated levels of alpha 2- and beta 1-subun it mRNAs, representing 256 and 177%, respectively, those of controls. For the tg cortex, the enhanced expression of GABA(A) receptor alpha 2 and beta 1 subunits correlates with recombinant subtypes known to hav e low affinity for 2-oxoquazepam and impaired binding of TBPS. These a berrant properties of GABA(A) receptors could influence the developmen t or propagation of phenotypic seizures in the tottering mouse. (C) 19 97 Elsevier Science B.V.