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

Isabella Ferando; Istvan Mody

doi:10.1016/j.neuropharm.2014.09.010

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

Neuropharmacology. 2015 Jan:88:91-8. doi: 10.1016/j.neuropharm.2014.09.010. Epub 2014 Sep 28.

Authors

Isabella Ferando¹, Istvan Mody²

Affiliations

¹ 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.
² 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.

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.

Keywords: CA3 interneurons; DS-2; Delta subunit; GABA(A) receptors pharmacology; Gamma oscillations; Neurosteroids; Parvalbumin; Tonic inhibition.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Benzamides / pharmacology
CA3 Region, Hippocampal / drug effects
CA3 Region, Hippocampal / physiology*
GABA Modulators / pharmacology
Gamma Rhythm / drug effects
Gamma Rhythm / physiology*
Immunohistochemistry
Interneurons / drug effects
Interneurons / physiology*
Male
Mice, Transgenic
Microelectrodes
Microscopy, Confocal
Neurotransmitter Agents / pharmacology
Parvalbumins / metabolism*
Pregnanolone / pharmacology
Receptors, GABA-A / deficiency*
Receptors, GABA-A / genetics
Tissue Culture Techniques

Substances

Benzamides
GABA Modulators
Gabrd protein, mouse
Neurotransmitter Agents
Parvalbumins
Receptors, GABA-A
Pregnanolone

Abstract

Publication types

MeSH terms

Substances

Grants and funding