Homeostatic Competition between Phasic and Tonic Inhibition

Wu, Xia; Huang, Lan-Ting; Wu, Zheng; Zhang, Ce; Jiang, Dongyun; Bai, Y.; Wang, Yun; Chen, Gong

doi:10.1074/jbc.m113.491464

Cited by 24 publications

(27 citation statements)

References 66 publications

(41 reference statements)

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“…We first transfected HEK293T cells with GABA A -R α2β3γ2 subunits for detecting GABA responses 11,12 . The hippocampal region was dissected out from WT or 5xFAD brain and made into homogenate by repeated freeze and thaw and sonication.…”

Section: Resultsmentioning

confidence: 99%

Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model

et al. 2014

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SUMMARY Amyloid plaques and tau tangles are common pathological hallmarks for Alzheimer’s disease (AD), however reducing Aβ production failed to relieve the symptoms of AD patients. Here we report a high GABA (γ-aminobutyric acid) content in reactive astrocytes in the dentate gyrus (DG) of a mouse model for AD (5xFAD) that results in increased tonic inhibition and memory deficit. We also confirm in human AD patient brains that dentate astrocytes have a high GABA content, suggesting that high astrocytic GABA level may be a novel biomarker and a potential diagnostic tool for AD. The excessive GABA in 5xFAD astrocytes is released through an astrocyte-specific GABA transporter GAT3/4, and significantly enhanced tonic GABA inhibition in dentate granule cells. Importantly, reducing tonic inhibition in 5xFAD mice rescues the impairment of long-term potentiation (LTP) and memory deficit. Thus, reducing tonic GABA inhibition in the DG may lead to a novel therapy for Alzheimer’s disease.

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Section: Resultsmentioning

confidence: 99%

Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model

et al. 2014

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“…The mechanisms underlying the phenomenon of homeostatic plasticity of inhibitory neuron excitability and output are poorly understood, including how and to which extent synaptic and extrasynaptic GABA A Rs interact with each other to balance tonic and phasic inhibition [ 14 ]. In previous studies overexpression of α 6 βδ or α 5 βγ 2 receptors at extrasynaptic sites in hippocampal neurons have not only been shown to result in increased tonic currents but also in significantly decreased synaptic GABA A R responses [ 72 , 73 ]. In one of these studies, the reduction in synaptic transmission was ascribed to competition between extrasynaptic and synaptic receptors for a limited number of receptor slots at the neuron surface [ 73 ].…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of GABAA receptor-mediated modulation of cortical neuron network activity in microelectrode array recordings

et al. 2017

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The numerous γ-aminobutyric acid type A receptor (GABAAR) subtypes are differentially expressed and mediate distinct functions at neuronal level. In this study we have investigated GABAAR-mediated modulation of the spontaneous activity patterns of primary neuronal networks from murine frontal cortex by characterizing the effects induced by a wide selection of pharmacological tools at a plethora of activity parameters in microelectrode array (MEA) recordings. The basic characteristics of the primary cortical neurons used in the recordings were studied in some detail, and the expression levels of various GABAAR subunits were investigated by western blotting and RT-qPCR. In the MEA recordings, the pan-GABAAR agonist muscimol and the GABABR agonist baclofen were observed to mediate phenotypically distinct changes in cortical network activity. Selective augmentation of αβγ GABAAR signaling by diazepam and of δ-containing GABAAR (δ-GABAAR) signaling by DS1 produced pronounced changes in the majority of the activity parameters, both drugs mediating similar patterns of activity changes as muscimol. The apparent importance of δ-GABAAR signaling for network activity was largely corroborated by the effects induced by the functionally selective δ-GABAAR agonists THIP and Thio-THIP, whereas the δ-GABAAR selective potentiator DS2 only mediated modest effects on network activity, even when co-applied with low THIP concentrations. Interestingly, diazepam exhibited dramatically right-shifted concentration-response relationships at many of the activity parameters when co-applied with a trace concentration of DS1 compared to when applied alone. In contrast, the potencies and efficacies displayed by DS1 at the networks were not substantially altered by the concomitant presence of diazepam. In conclusion, the holistic nature of the information extractable from the MEA recordings offers interesting insights into the contributions of various GABAAR subtypes/subgroups to cortical network activity and the putative functional interplay between these receptors in these neurons.

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“…Much remains to be learned about the functions and potential interactions of GABA A receptor subtypes within the SCN and throughout the CNS (Wu et al, 2013). Given that subunit composition dictates GABA A receptor subcellular location and function, characterization of GABA A receptor composition is critical to understanding GABAergic communication within the SCN.…”

Section: Gaba Receptorsmentioning

confidence: 99%

The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus

Albers

Walton

Gamble

et al. 2017

Frontiers in Neuroendocrinology

133

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Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extracellular levels of GABA within the SCN are determined by a complex interaction of synthesis and transport, as well as synaptic and non-synaptic release. The response to GABA is mediated by GABAA receptors that respond to both phasic and tonic GABA release and that can produce excitatory as well as inhibitory cellular responses. GABA also influences circadian control through the exclusively inhibitory effects of GABAB receptors. Both GABA and neuropeptide signaling occur within the SCN, although the functional consequences of the interactions of these signals are not well understood. This review considers the role of GABA in the circadian pacemaker, in the mechanisms responsible for the generation of circadian rhythms, in the ability of non-photic stimuli to reset the phase of the pacemaker, and in the ability of the day-night cycle to entrain the pacemaker.

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Homeostatic Competition between Phasic and Tonic Inhibition

Cited by 24 publications

References 66 publications

Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model

Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model

Functional characterization of GABAA receptor-mediated modulation of cortical neuron network activity in microelectrode array recordings

The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus

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