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

d-subunit containing extrasynaptic GABAA 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 inhi- bition, we used a new positive modulator, AA29504, of d-subunit containing GABAA 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 mM) caused a 4.2-fold potentiation of a tonic current induced by THIP (1 mM), while interneurons showed a potentiation of 2.6-fold. Moreover, AA29504 (1 mM) increased the amplitude and prolonged the decay of miniature inhibitory postsynaptic currents (mIPSCs) in granule cells, and this effect was abolished by Zn 2þ (15 mM). AA29504 (1 mM) also induced a small tonic current (12.7 � 3.2 pA) per se, and when evaluated in a nominally GABA-free environment using Ca 2þ imaging in cultured neurons, AA29504 showed GABAA 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 d-containing GABAA receptors to enhance tonic inhibition, and possibly recruits perisynaptic d-containing receptors to participate in synaptic phasic inhibition in dentate gyrus.