Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits

Background: Multiple cognitive and psychiatric disorders are associated with an increased tonic inhibitory conductance that is generated by alpha 5 subunit-containing gamma-aminobutyric acid type A (alpha 5 GABA(A)) receptors. Negative allosteric modulators that inhibit alpha 5 GABA(A) receptors (alpha 5-NAMs) are being developed as treatments for these disorders. The effects of alpha 5-NAMs have been studied on recombinant GABA(A) receptors expressed in non-neuronal cells; however, no study has compared drug effects on the tonic conductance generated by native GABA(A) receptors in neurones, which was the goal of this study.Methods: The effects of five alpha 5-NAMs (basmisanil, Ono-160, L-655,708, alpha 5IA, and MRK-016) on tonic current evoked by a low concentration of GABA were studied using whole-cell recordings in cultured mouse hippocampal neurones. Drug effects on current evoked by a saturating concentration of GABA and on miniature inhibitory postsynaptic currents (mIPSCs) were also examined.Results: The alpha 5-NAMs caused a concentration-dependent decrease in tonic current. The potencies varied as the inhibitory concentration for 50% inhibition (IC50) of basmisanil (127 nM) was significantly higher than those of the other compounds (0.4-0.8 nM). In contrast, the maximal efficacies of the drugs were similar (35.5-51.3% inhibition). The alpha 5-NAMs did not modify current evoked by a saturating GABA concentration or mIPSCs.Conclusions: Basmisanil was markedly less potent than the other alpha 5-NAMs, an unexpected result based on studies of recombinant alpha 5 GABA(A) receptors. Studying the effects of alpha 5 GABA(A) receptor-selective drugs on the tonic inhibitory current in neurones could inform the selection of compounds for future clinical trials.