Synaptic Release Generates a Tonic GABA<sub>A</sub>Receptor-Mediated Conductance That Modulates Burst Precision in Thalamic Relay Neurons

Bright, Damian P.; Aller, M. Isabel; Brickley, Stephen G.

doi:10.1523/jneurosci.5100-06.2007

Cited by 108 publications

(114 citation statements)

References 48 publications

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“…Synaptic spillover from action potential-dependent vesicular release of neurotransmitter is thought to be a primary source for the ambient GABA responsible for activating extrasynaptic tonic GABA A receptors (Brickley et al, 1996;Wall and Usowicz, 1997;Bright et al, 2007). In agreement with these findings, application of a sodium channel blocker mimicked the results obtained by BIC application (Fig.…”

Section: Resultssupporting

confidence: 82%

“…Subunit composition also appears to be specific to both the brain subregion and cellular subtype of the neurons on which they are located. For example, extrasynaptic GABA A receptors containing the ␦ subunit have been shown to mediate tonic inhibition in cerebellar granule cells (for review, see Farrant and Nusser, 2005), dentate gyrus granule cells (Wei et al, 2003), hippocampal interneurons (Semyanov et al, 2003;, and thalamocortical projection neurons (Belelli et al, 2005;Cope et al, 2005;Jia et al, 2005;Bright et al, 2007). Although immunohistochemical studies of GABA A receptor subunit expression have been limited to the rat, these studies have demonstrated diffuse expression patterns of the ␦ subunit in the striatum (Pirker et al, 2000;Schwarzer et al, 2001).…”

Section: Extrasynaptic Gaba a Receptors In Msnsmentioning

confidence: 99%

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Differential Tonic GABA Conductances in Striatal Medium Spiny Neurons

Ade¹,

Janssen²,

Ortinski³

et al. 2008

J. Neurosci.

150

182

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Section: Resultssupporting

confidence: 82%

Section: Extrasynaptic Gaba a Receptors In Msnsmentioning

confidence: 99%

Differential Tonic GABA Conductances in Striatal Medium Spiny Neurons

Ade¹,

Janssen²,

Ortinski³

et al. 2008

J. Neurosci.

150

182

View full text Add to dashboard Cite

show abstract

“…It is apparent that tonic inhibition is essential for dynamically regulating the neuronal output, frequency of firing, and gain control of neurotransmission (12)(13)(14)(15)(16)(17)(18)(19). In addition, extrasynaptic GABA A Rs have been further shown to be targets for a wide range of endogenous and pharmacological agents, such as neurosteroids, anesthetics, ethanol, and anticonvulsants (20 -23).…”

Section: ␥-Aminobutyric Acid Type a Receptors (Gaba A Rs)mentioning

confidence: 99%

Protein Kinase C Phosphorylation Regulates Membrane Insertion of GABAA Receptor Subtypes That Mediate Tonic Inhibition

Abramian

Comenencia-Ortiz

Vithlani

et al. 2010

Journal of Biological Chemistry

123

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Tonic inhibition in the brain is mediated largely by specialized populations of extrasynaptic receptors, ␥-aminobutyric acid receptors (GABA A Rs). In the dentate gyrus region of the hippocampus, tonic inhibition is mediated primarily by GABA A R subtypes assembled from ␣4␤2/3 with or without the ␦ subunit. Although the gating of these receptors is subject to dynamic modulation by agents such as anesthetics, barbiturates, and neurosteroids, the cellular mechanisms neurons use to regulate their accumulation on the neuronal plasma membrane remain to be determined. Using immunoprecipitation coupled with metabolic labeling, we demonstrate that the ␣4 subunit is phosphorylated at Ser 443 by protein kinase C (PKC) in expression systems and hippocampal slices. In addition, the ␤3 subunit is phosphorylated on serine residues 408/409 by PKC activity, whereas the ␦ subunit did not appear to be a PKC substrate. We further demonstrate that the PKC-dependent increase of the cell surface expression of ␣4 subunit-containing GABA A Rs is dependent on Ser 443 . Mechanistically, phosphorylation of Ser 443 acts to increase the stability of the ␣4 subunit within the endoplasmic reticulum, thereby increasing the rate of receptor insertion into the plasma membrane. Finally, we show that phosphorylation of Ser 443 increases the activity of ␣4 subunit-containing GABA A Rs by preventing current run-down. These results suggest that PKC-dependent phosphorylation of the ␣4 subunit plays a significant role in enhancing the cell surface stability and activity of GABA A R subtypes that mediate tonic inhibition. ␥-Aminobutyric acid type A receptors (GABA A Rs)2 constitute the major inhibitory ligand-gated receptors in the adult central nervous system and are responsible for both phasic and tonic forms of inhibition (1). These receptors are pentameric, anion-selective ion channels that can be assembled from eight subunit classes: ␣(1-6), ␤(1-3), ␥(1-3), ␦, ⑀, , , and (1-3)(2-3). This large number of receptor subunits provides the basis for a significant degree of heterogeneity of GABA A R structure and function. However, previous studies suggest that in the brain, the majority of phasic inhibition is dependent upon a few GABA A Rs subunits, namely the ␣, ␤, and ␥2 subunits located within synaptic sites (2, 3). In the adult brain, these receptors are specific targets for brief exposures to high concentrations of GABA, resulting in short lived, but significant, hyperpolarization. In contrast, tonic inhibition is characterized by a sustained reduction in the cell's input resistance, effectively reducing the probability of action potential generation (1, 4). Tonic inhibition is the result of persistent activation by GABA A Rs consisting primarily of ␣, ␤, and ␦ subunits located within peri-or extrasynaptic sites (1). With respect to specific brain regions, extrasynaptic GABA A Rs that mediate tonic inhibition in the thalamus and dentate gyrus of the hippocampus are composed of the ␣4 and ␤2/3 subunits with or without the ␦ subunit (5-9). Verificati...

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“…In addition, a tonic form of inhibition in thalamocortical relay neurons is generated via persistent activation of extrasynaptic ␣ 4 ␤ 2 ␦ receptors (Porcello et al, 2003;Belelli et al, 2005;Cope et al, 2005;Jia et al, 2005Jia et al, , 2008Chandra et al, 2006;Bright et al, 2007;Peden et al, 2008). In the present study, we compared the actions of eszopiclone and zolpidem on these three populations of GABA A -Rs in the mouse thalamus.…”

mentioning

confidence: 99%

The Modulation of Synaptic GABA_A Receptors in the Thalamus by Eszopiclone and Zolpidem

Fan¹,

Goldstein²,

Harrison³

2008

J Pharmacol Exp Ther

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Eszopiclone (Lunesta; Sepracor, Marlborough, MA) and zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)-imidazo(1,2-a)pyridine-3-acetamide] are among the most commonly prescribed hypnotics in use in the United States. The thalamus plays a pivotal role in sleep regulation and rhythmicity. Two distinct subtypes of synaptic GABA A receptors (GABA A -Rs), ␣ 1 ␤ 2 ␥ 2 and ␣ 3 ␤ 3 ␥ 2 , are expressed in thalamocortical relay neurons and in interneurons of the RTN (reticular thalamic nucleus), respectively. Thalamocortical neurons also express extrasynaptic GABA A -Rs composed of ␣ 4 ␤ 2 ␦ subunits. In this study, we compared the effects of eszopiclone and zolpidem on miniature inhibitory postsynaptic currents (IPSCs), spontaneous IPSCs, and tonic inhibition in the mouse thalamus. Eszopiclone (0.1-1 M) slowed the decay phase of IPSCs recorded from RTN neurons, whereas zolpidem was less effective and increased the decay time constant only at Ն0.3 M. IPSCs of RTN neurons were more sensitive to eszopiclone than zolpidem at all concentrations tested. On the other hand, IPSCs of relay neurons in the ventrobasal nucleus (VB) were more sensitive to zolpidem than eszopiclone. Zolpidem (0.1-1 M) prolonged the decay of IPSCs from VB neurons, whereas eszopiclone increased the decay time constant only at Ն0.3 M. Neither of these two hypnotics affected tonic inhibition in relay neurons. Our results demonstrate that eszopiclone has greater efficacy at synaptic GABA A -Rs of RTN neurons than in relay neurons, whereas zolpidem exerts bigger effects on relay neurons than RTN neurons. This distinct pattern of activity on thalamic neurons may contribute to some of the observed differences in the clinical effects of these two hypnotics.

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Synaptic Release Generates a Tonic GABA_AReceptor-Mediated Conductance That Modulates Burst Precision in Thalamic Relay Neurons

Cited by 108 publications

References 48 publications

Differential Tonic GABA Conductances in Striatal Medium Spiny Neurons

Differential Tonic GABA Conductances in Striatal Medium Spiny Neurons

Protein Kinase C Phosphorylation Regulates Membrane Insertion of GABAA Receptor Subtypes That Mediate Tonic Inhibition

The Modulation of Synaptic GABA_A Receptors in the Thalamus by Eszopiclone and Zolpidem

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Synaptic Release Generates a Tonic GABAAReceptor-Mediated Conductance That Modulates Burst Precision in Thalamic Relay Neurons

Cited by 108 publications

References 48 publications

Differential Tonic GABA Conductances in Striatal Medium Spiny Neurons

Differential Tonic GABA Conductances in Striatal Medium Spiny Neurons

Protein Kinase C Phosphorylation Regulates Membrane Insertion of GABAA Receptor Subtypes That Mediate Tonic Inhibition

The Modulation of Synaptic GABAA Receptors in the Thalamus by Eszopiclone and Zolpidem

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Synaptic Release Generates a Tonic GABA_AReceptor-Mediated Conductance That Modulates Burst Precision in Thalamic Relay Neurons

The Modulation of Synaptic GABA_A Receptors in the Thalamus by Eszopiclone and Zolpidem