4.6 Article

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

期刊

BRITISH JOURNAL OF ANAESTHESIA
卷 126, 期 3, 页码 674-683

出版社

ELSEVIER SCI LTD
DOI: 10.1016/j.bja.2020.11.032

关键词

alpha 5 GABA(A) receptor; hippocampus; negative allosteric modulator; neurocognitive disorder; synaptic inhibition; tonic inhibition

资金

  1. Canadian Institutes of Health Research [FDN-154312]
  2. Ontario Graduate Scholarship
  3. Frederick Banting and Charles Best Canada Graduate Scholarship-Master's Program
  4. Wellcome Trust
  5. Welsh Government/European Regional Development Fund
  6. Dr Kirk Weber Research Award in Anaesthesia
  7. Canada Graduate Scholarship-Doctoral Program from the Canadian Institutes of Health Research

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The study investigated the effects of five alpha 5-NAMs on tonic current in mouse hippocampal neurones. Results showed a concentration-dependent decrease in tonic current, with variations in potencies among the compounds. The study suggests that 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.
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.

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