title: Ovarian cycle-linked plasticity of δ-GABAA receptor subunits in hippocampal interneurons affects γ oscillations in vivo.
abstract: GABAA receptors containing δ subunits (δ-GABAARs) are GABA-gated ion channels with extra- and perisynaptic localization, strong sensitivity to neurosteroids (NS), and a high degree of plasticity. In selective brain regions they are expressed on specific principal cells and interneurons (INs), and generate a tonic conductance that controls neuronal excitability and oscillations. Plasticity of δ-GABAARs in principal cells has been described during states of altered NS synthesis including acute stress, puberty, ovarian cycle, pregnancy and the postpartum period, with direct consequences on neuronal excitability and network dynamics. The defining network events implicated in cognitive function, memory formation and encoding are γ oscillations (30-120 Hz), a well-timed loop of excitation and inhibition between principal cells and PV-expressing INs (PV + INs). The δ-GABAARs of INs can modify γ oscillations, and a lower expression of δ-GABAARs on INs during pregnancy alters γ frequency recorded in vitro. The ovarian cycle is another physiological event with large fluctuations in NS levels and δ-GABAARs. Stages of the cycle are paralleled by swings in memory performance, cognitive function, and mood in both humans and rodents. Here we show δ-GABAARs changes during the mouse ovarian cycle in hippocampal cell types, with enhanced expression during diestrus in principal cells and specific INs. The plasticity of δ-GABAARs on PV-INs decreases the magnitude of γ oscillations continuously recorded in area CA1 throughout several days in vivo during diestrus and increases it during estrus. Such recurring changes in γ magnitude were not observed in non-cycling wild-type (WT) females, cycling females lacking δ-GABAARs only on PV-INs (PV-Gabrd (-/-)), and in male mice during a time course equivalent to the ovarian cycle. Our findings may explain the impaired memory and cognitive performance experienced by women with premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD).
authors.affiliation: Department of Neurology, The David Geffen School of Medicine, University of California at Los Angeles Los Angeles, CA, USA.
authors.forename: Albert M I
authors.initials: AM
authors.lastname: Barth
authors.affiliation: Department of Neurology, The David Geffen School of Medicine, University of California at Los Angeles Los Angeles, CA, USA ; Interdepartmental Graduate Program in Molecular, Cellular, and Integrative Physiology, University of California at Los Angeles Los Angeles, CA, USA.
authors.forename: Isabella
authors.initials: I
authors.lastname: Ferando
authors.affiliation: Department of Neurology, The David Geffen School of Medicine, University of California at Los Angeles Los Angeles, CA, USA ; Department of Physiology, The David Geffen School of Medicine, University of California at Los Angeles Los Angeles, CA, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Mody
keywords: GABAA receptor; PMDD; PMS; delta subunit; gamma oscillations; ovarian cycle; parvalbumin; tonic inhibition