Positive modulation of δ-subunit containing GABA(A) receptors in mouse neurons

Neuropharmacology
Irina VardyaK Jensen

Abstract

δ-subunit containing extrasynaptic GABA(A) receptors are potential targets for modifying neuronal activity in a range of brain disorders. With the aim of gaining more insight in synaptic and extrasynaptic inhibition, we used a new positive modulator, AA29504, of δ-subunit containing GABA(A) receptors in mouse neurons in vitro and in vivo. Whole-cell patch-clamp recordings were carried out in the dentate gyrus in mouse brain slices. In granule cells, AA29504 (1 μM) caused a 4.2-fold potentiation of a tonic current induced by THIP (1 μM), while interneurons showed a potentiation of 2.6-fold. Moreover, AA29504 (1 μM) increased the amplitude and prolonged the decay of miniature inhibitory postsynaptic currents (mIPSCs) in granule cells, and this effect was abolished by Zn²⁺ (15 μM). AA29504 (1 μM) also induced a small tonic current (12.7 ± 3.2 pA) per se, and when evaluated in a nominally GABA-free environment using Ca²⁺ imaging in cultured neurons, AA29504 showed GABA(A) receptor agonism in the absence of agonist. Finally, AA29504 exerted dose-dependent stress-reducing and anxiolytic effects in mice in vivo. We propose that AA29504 potentiates δ-containing GABA(A) receptors to enhance tonic inhibition, and possibly recruits perisy...Continue Reading

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Citations

Jan 28, 2014·British Journal of Pharmacology·Benjamin K LauGeoffrey M Drew
Aug 17, 2014·Neuropharmacology·Paul D WhissellBeverley A Orser
Mar 17, 2017·Basic & Clinical Pharmacology & Toxicology·Christina B Falk-PetersenPetrine Wellendorph
Jan 30, 2018·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Andrew N ClarksonMary Chebib
Jun 24, 2020·Scientific Reports·Christina Birkedahl Falk-PetersenPetrine Wellendorph

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