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 principal cells and interneurons (INs) of the central nervous system. δ-GABAARs comprise α4 subunits on principal cells of the neocortex and hippocampus, whereas they usually contain α1 on various INs. δ-GABAARs are highly plastic and exhibit a unique pharmacology, being insensitive to benzodiazepines, but sensitive to low concentrations of neurosteroids (NS). The neuroactive forms of several steroid hormones, NS act on δ-GABAARs as potent positive allosteric modulators leading to changes in neuronal excitability and network synchrony. In fact, δ-GABAARs on INs have been shown to control the dynamics of γ oscillations. During times of altered NS production, including stress, puberty, ovarian cycle and pregnancy, δ-GABAAR expression varies in different neurons regardless of the α subunits they contain. This plasticity has direct consequences for network functioning. In particular, plasticity of these receptors in pregnancy and the postpartum period affects CA3 γ oscillation frequencies (recorded in vitro), and during the ovarian cycle they underlie fluctuations in the amplitude of CA1 γ oscillations (recorded in vivo). Most δ-GABAAR-expressing INs in CA3 stratum pyramidale (SP) are parvalbumin (PV)+INs, whose fundamental role in γ oscillation 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. By means of immunohistochemistry we show that PV expression in PV-Gabrd−/− and PV-Gabrd+/− mice remains unaltered. Additionally, we confirm the absence of δ-GABAARs specifically from PV+INs. We find that in both PV-Gabrd−/− and PV-Gabrd+/− mice, CA3 γ oscillation frequencies measured in vitro were increased compared to Cre−/− controls. The increased frequencies could be lowered to control levels in PV-Gabrd+/− by the NS allopregnanolone (3α,5α-tetrahydroprogesterone, ALLO, 100 nM) but not by 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.

Altered behavioral responses to gamma‐aminobutyric acid pharmacological agents in a mouse model of Huntington's disease

“…9,10 Interestingly, although the underlying mechanism remains elusive, elevated gamma oscillation in the brain is associated with cognitive deficits and disease progression in HD mice. 43,44 Because abnormal gamma oscillation occurred in d-subunit null mice, 45,46 and d subunit deficiency occurred in HD mice, lower levels of d subunit-containing GABA A Rs and the resulting poor tonic inhibition in HD brains might contribute to the development of abnormal gamma oscillation and motor/behavioral dysfunctions in HD.…”

Input-dependent modulation of MEG gamma oscillations reflects gain control in the visual cortex

“…Neurophysiological studies in animals suggest that the frequency of gamma oscillations is controlled mainly through changes in the tonic excitatory state of fast-spiking inhibitory cells 17,18 . We therefore suggest the effect of rising excitatory drive on MEG gamma frequency in the current study is mediated primarily through the increasing excitation of inhibitory neurons.…”

“…The frequency of gamma oscillations increases monotonically with increasing intensity of visual input, such as visual contrast 9,[12][13][14] or motion velocity/temporal frequency 15,16 . Experimental studies in animals suggest that an increase of the tonic excitability of inhibitory interneurons may account for the stimulation-driven increase in gamma frequency 17,18 . On the other hand, the power of gamma oscillations in local field potentials (LFP) of non-human primates initially increases with contrast 9,13,14 or temporal frequency 19 and then attenuates at higher stimulation intensities.…”

Interneuronal δ-GABAA receptors regulate binge drinking and are necessary for the behavioral effects of early withdrawal

“…Animals with parvalbumin-specific deletion of the GABA A -δ subunit (PV:δ −/− ) were generated by crossing floxed Gabrd mice [36] with PV-Cre mice obtained from Jackson's Lab (Stock #012358). These PV:δ −/− mice have recently been characterized [37,38]. Genotyping for PV-Cre was performed in-house using the primers listed below.…”