Spontaneously Opening GABA A Channels in CA1 Pyramidal Neurones of Rat Hippocampus

Birnir, Bryndis; Everitt, Andrea B.; Lim, M.; Gage, Peter W.

doi:10.1007/s002320001028

Cited by 48 publications

(46 citation statements)

References 35 publications

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“…Thus, GABA A receptors containing the ␤ 1 subunit may be inhibited by loreclezole or stay unaffected by it. Spontaneously opening GABA A receptors are present in hippocampal neurons (Macdonald et al, 1989;Birnir et al, 2000). It is possible that spontaneously opening GABA A receptors participate in the tonic current described in this article.…”

Section: Discussionmentioning

confidence: 82%

High-Affinity, Slowly Desensitizing GABA_A Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells

Mtchedlishvili

2005

Mol Pharmacol

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The tonic form of GABA-mediated inhibition requires the presence of slowly desensitizing GABA A receptors with high affinity, which has not yet been directly demonstrated in hippocampal neurons. Low concentration of GABA (1 M) persistently increased baseline noise, increased membrane slope conductance, but did not affect spontaneous inhibitory postsynaptic currents (sIPSCs) in dentate granule cells (DGCs). Higher concentrations of GABA (10 -100 M) desensitized synaptic currents quickly, and there was a large residual current. Saturating concentration of GABA (1 mM) completely desensitized synaptic currents and revealed a slowly desensitizing, persistent current. Penicillin (300 M) inhibited baseline noise without affecting mean current and inhibited decay time of sIPSCs. GABA A receptors mediating baseline noise in DGCs were sensitive to allopregnanolone, furosemide, and loreclezole and insensitive to diazepam and zolpidem. These studies demonstrate persistently open GABA A receptors on DGCs with high affinity for GABA, slow desensitization rate, and pharmacological properties similar to those of recombinant receptors containing ␣ 4 , ␤ 1 , and the ␦ subunits.

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Section: Discussionmentioning

confidence: 82%

High-Affinity, Slowly Desensitizing GABA_A Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells

Mtchedlishvili

2005

Mol Pharmacol

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“…Statistical significance compared with the density of current inhibited by picrotoxin for each GABA A receptor type was determined using a one-way ANOVA with post hoc Tukey test: ‫,ءء‬ p Ͻ 0.01 and ‫,ءءء‬ p Ͻ 0.001. side-out patch recordings from pituitary intermediate lobe cells (Taleb et al, 1987) and in cell-attached patch recordings from hippocampal pyramidal neurons (Birnir et al, 2000) and hypothalamic neurons (Jones et al, 2006). We found that spontaneous channel activity in outside-out patches excised from pyramidal neurons were independent of GABA, persisted for prolonged time periods after patch excision, were resistant to gabazine, and were abolished by picrotoxin.…”

Section: (Described Under Materials and Methods)mentioning

confidence: 82%

Tonically Active GABA_A Receptors in Hippocampal Pyramidal Neurons Exhibit Constitutive GABA-Independent Gating

McCartney

Deeb²,

Henderson³

et al. 2006

Mol Pharmacol

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Phasic and tonic inhibitory currents of hippocampal pyramidal neurons exhibit distinct pharmacological properties. Picrotoxin and bicuculline methiodide inhibited both components, consistent with a role for GABA A receptors; however, gabazine, at a concentration that abolished miniature GABAergic inhibitory postsynaptic currents and responses to exogenous GABA, had no effect on tonic currents. Because all GABA-activated GABA A receptors in pyramidal neurons are gabazine-sensitive, it follows that tonic currents are not GABA-activated. Furthermore, picrotoxin-sensitive spontaneous single-channel events recorded from outside-out patches had the same chord conductance as GABA-activated channels and were gabazineresistant. Therefore, we hypothesize that GABA A receptors, constitutively active in the absence of GABA, mediate tonic current; the failure of gabazine to block tonic current reflects a lack of negative intrinsic efficacy of the antagonist. We compared the negative efficacies of bicuculline and gabazine using the general anesthetic propofol to directly activate GABA A receptors native to pyramidal neurons or ␣1␤3␥2 receptors recombinantly expressed in human embryonic kidney 293 cells. Propofol activated gabazine-resistant, bicuculline-sensitive currents when applied to either preparation. Although gabazine had negligible efficacy as an inhibitor of propofol-activated currents, it prevented inhibition by bicuculline, which acts as an inverse agonist inhibiting GABA-independent gating. Recombinant ␣1␤1/3␥2 receptors also mediated agonist-independent tonic currents that were resistant to gabazine and inhibited by bicuculline. Thus, gabazine is a competitive antagonist with negligible negative efficacy and is therefore unable to inhibit GABA A receptors that are active in the absence of GABA because of either anesthetic or spontaneous gating. Moreover, spontaneously active GABA A receptors mediate gabazine-resistant tonic currents in pyramidal neurons.

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“…8A below) into a set of differential equations and solved them numerically. Because in the absence of agonist receptors can spontaneously open at very low probability (25)(26)(27), for simulation convenience it was assumed as the initial condition, i.e. at t ϭ 0 no bound or open receptors were present.…”

Section: Methodsmentioning

confidence: 99%

Declusterization of GABAA Receptors Affects the Kinetic Properties of GABAergic Currents in Cultured Hippocampal Neurons

Petrini

Zacchi

Barberis

et al. 2003

Journal of Biological Chemistry

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Spontaneously Opening GABA A Channels in CA1 Pyramidal Neurones of Rat Hippocampus

Cited by 48 publications

References 35 publications

High-Affinity, Slowly Desensitizing GABA_A Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells

High-Affinity, Slowly Desensitizing GABA_A Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells

Tonically Active GABA_A Receptors in Hippocampal Pyramidal Neurons Exhibit Constitutive GABA-Independent Gating

Declusterization of GABAA Receptors Affects the Kinetic Properties of GABAergic Currents in Cultured Hippocampal Neurons

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Spontaneously Opening GABA A Channels in CA1 Pyramidal Neurones of Rat Hippocampus

Cited by 48 publications

References 35 publications

High-Affinity, Slowly Desensitizing GABAA Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells

High-Affinity, Slowly Desensitizing GABAA Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells

Tonically Active GABAA Receptors in Hippocampal Pyramidal Neurons Exhibit Constitutive GABA-Independent Gating

Declusterization of GABAA Receptors Affects the Kinetic Properties of GABAergic Currents in Cultured Hippocampal Neurons

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High-Affinity, Slowly Desensitizing GABA_A Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells

High-Affinity, Slowly Desensitizing GABA_A Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells

Tonically Active GABA_A Receptors in Hippocampal Pyramidal Neurons Exhibit Constitutive GABA-Independent Gating