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

• Published in: British journal of anaesthesia : BJA Vol. 126; no. 3; p. 674
• Main Authors: Manzo, Marc A, Wang, Dian-Shi, Li, Winston W, Pinguelo, Arsène, Popa, Mariana O, Khodaei, Shahin, Atack, John R, Ross, Ruth A, Orser, Beverley A
• Format: Journal Article
• Language: English
• Published: England 01-03-2021
• Subjects: Allosteric Regulation; Animals; Cells, Cultured; Cognition - drug effects; Cognitive Dysfunction - drug therapy; Dose-Response Relationship, Drug; GABA-A Receptor Antagonists - pharmacology; Hippocampus - drug effects; Hippocampus - metabolism; Inhibitory Postsynaptic Potentials - drug effects; Mice; Neurons - drug effects; Neurons - metabolism; Patch-Clamp Techniques; Receptors, GABA-A - metabolism; negative allosteric modulator; tonic inhibition; α5 GABA(A) receptor; hippocampus; synaptic inhibition; neurocognitive disorder
• ISSN: 1471-6771
• DOI: 10.1016/j.bja.2020.11.032

Multiple cognitive and psychiatric disorders are associated with an increased tonic inhibitory conductance that is generated by α5 subunit-containing γ-aminobutyric acid type A (α5 GABA
) receptors. Negative allosteric modulators that inhibit α5 GABA
receptors (α5-NAMs) are being developed as treatments for these disorders. The effects of α5-NAMs have been studied on recombinant GABA
receptors expressed in non-neuronal cells; however, no study has compared drug effects on the tonic conductance generated by native GABA
receptors in neurones, which was the goal of this study.
The effects of five α5-NAMs (basmisanil, Ono-160, L-655,708, α5IA, 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.
The α5-NAMs caused a concentration-dependent decrease in tonic current. The potencies varied as the inhibitory concentration for 50% inhibition (IC
) 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 α5-NAMs did not modify current evoked by a saturating GABA concentration or mIPSCs.
Basmisanil was markedly less potent than the other α5-NAMs, an unexpected result based on studies of recombinant α5 GABA
receptors. Studying the effects of α5 GABA
receptor-selective drugs on the tonic inhibitory current in neurones could inform the selection of compounds for future clinical trials.