Positive modulation of δ-subunit containing GABAA receptors in mouse neurons

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 Zn 2+ (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 Ca 2+ 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 perisynaptic δ-containing receptors to participate in synaptic phasic inhibition in dentate gyrus.