title: Positive modulation of δ-subunit containing GABA(A) 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 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 perisynaptic δ-containing receptors to participate in synaptic phasic inhibition in dentate gyrus.
authors.affiliation: Synaptic Physiology Laboratory, Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Irina
authors.initials: I
authors.lastname: Vardya
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hoestgaard-Jensen
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Nieto-Gonzalez
authors.forename: Zita
authors.initials: Z
authors.lastname: Dósa
authors.forename: Kim
authors.initials: K
authors.lastname: Boddum
authors.forename: Mai Marie
authors.initials: MM
authors.lastname: Holm
authors.forename: Toni D
authors.initials: TD
authors.lastname: Wolinsky
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jones
authors.forename: Nils Ole
authors.initials: NO
authors.lastname: Dalby
authors.forename: Bjarke
authors.initials: B
authors.lastname: Ebert
authors.forename: Kimmo
authors.initials: K
authors.lastname: Jensen
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003627:Data Interpretation, Statistical; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects; D055724:Electrophysiological Phenomena; D005334:Fever / Q000209:etiology; D018682:GABA Agents / Q000378:metabolism / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018682:GABA Agents; D018755:GABA Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; C015542:gaboxadol; D002118:Calcium