In vitro gamma oscillations following partial and complete ablation of δ subunit-containing GABAA receptors from parvalbumin interneurons

Perisynaptic and extrasynaptic delta subunit-containing GABA(A) receptors (delta-GABA(A)Rs) mediate tonic conductances in many neurons. On principal cells of the neocortex and hippocampus they comprise alpha 4 subunits, whereas they usually contain alpha 1 on various interneurons. Specific characteristics of delta-GABA(A)Rs are their pharmacology and high plasticity. In particular delta-GABA(A)Rs are sensitive to low concentrations of neurosteroids (NS) and during times of altered NS production (stress, puberty, ovarian cycle and pregnancy) delta-GABA(A)Rs expression varies in many neurons regardless of the alpha subunits they contain, with direct consequences for neuronal excitability and network synchrony. For example delta-GABA(A)Rs plasticity on INs underlies modifications in hippocampal gamma oscillations during pregnancy or over the ovarian cycle. Most delta-GABA(A)R-expressing INs in CA3 stratum pyramidale (SP) are parvalbumin (PV) + INs, whose fundamental role in gamma oscillations generation and control has been extensively investigated. In this study we reduced or deleted delta-subunits in PV + INs, with the use of a PV/Cre-Gabrd/floxed genetic system. We find that in vitro CA3 gamma 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 (3 alpha,5 alpha-tetrahydroprogesterone, 100 nM) but not the synthetic delta-GABA(A)R positive allosteric modulator 4-Chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl] benzamide (DS-2, 10 mu M). This is consistent with the idea that DS-2, in contrast to ALLO, selectively targets delta 4/delta-GABA(A)Rs but not the alpha 1/delta-GABA(A)Rs found on INs. Therefore, development of drugs selective for IN-specific alpha 1/delta-GABA(A)Rs may be useful in neurological and psychiatric conditions correlated with altered PV + IN function and aberrant gamma oscillations. This article is part of the Special Issue entitled 'GABAergic Signaling in Health and Disease'. (C) 2014 Elsevier Ltd. All rights reserved.