title: In vitro gamma oscillations following partial and complete ablation of δ subunit-containing GABAA receptors from parvalbumin interneurons.
abstract: Perisynaptic and extrasynaptic δ subunit-containing GABAA receptors (δ-GABAARs) mediate tonic conductances in many neurons. On principal cells of the neocortex and hippocampus they comprise α4 subunits, whereas they usually contain α1 on various interneurons. Specific characteristics of δ-GABAARs are their pharmacology and high plasticity. In particular δ-GABAARs are sensitive to low concentrations of neurosteroids (NS) and during times of altered NS production (stress, puberty, ovarian cycle and pregnancy) δ-GABAARs expression varies in many neurons regardless of the α subunits they contain, with direct consequences for neuronal excitability and network synchrony. For example δ-GABAARs plasticity on INs underlies modifications in hippocampal γ oscillations during pregnancy or over the ovarian cycle. Most δ-GABAAR-expressing INs in CA3 stratum pyramidale (SP) are parvalbumin (PV) + INs, whose fundamental role in γ oscillations generation and control has been extensively investigated. In this study we reduced or deleted δ-subunits in PV + INs, with the use of a PV/Cre-Gabrd/floxed genetic system. We find that in vitro CA3 γ oscillations of both PV-Gabrd(+/-)and PV-Gabrd(-/-) mice are characterized by higher frequencies than WT controls. The increased frequencies could be lowered to control levels in PV-Gabrd(+/-) by the NS allopregnanolone (3α,5α-tetrahydroprogesterone, 100 nM) but not the synthetic δ-GABAAR positive allosteric modulator 4-Chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl] benzamide (DS-2, 10 μM). This is consistent with the idea that DS-2, in contrast to ALLO, selectively targets α4/δ-GABAARs but not the α1/δ-GABAARs found on INs. Therefore, development of drugs selective for IN-specific α1/δ-GABAARs may be useful in neurological and psychiatric conditions correlated with altered PV + IN function and aberrant γ oscillations.
authors.affiliation: Departments of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Interdepartmental Graduate Program in Molecular, Cellular, and Integrative Physiology, University of California, Los Angeles, CA, USA.
authors.forename: Isabella
authors.initials: I
authors.lastname: Ferando
authors.affiliation: Departments of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Departments of Physiology, The David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address: mody@ucla.edu.
authors.forename: Istvan
authors.initials: I
authors.lastname: Mody
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000502:physiology*; D018757:GABA Modulators / Q000494:pharmacology; D065818:Gamma Rhythm / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008822:Mice, Transgenic; D008839:Microelectrodes; D018613:Microscopy, Confocal; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010320:Parvalbumins / Q000378:metabolism*; D011280:Pregnanolone / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000172:deficiency* / Q000235:genetics; D046509:Tissue Culture Techniques
chemical_list: D001549:Benzamides; D018757:GABA Modulators; C583130:Gabrd protein, mouse; D018377:Neurotransmitter Agents; D010320:Parvalbumins; D011963:Receptors, GABA-A; D011280:Pregnanolone
keywords: CA3 interneurons; DS-2; Delta subunit; GABA(A) receptors pharmacology; Gamma oscillations; Neurosteroids; Parvalbumin; Tonic inhibition