scholarly journals GABAA Receptor α5 Subunits Contribute to GABAA,slow Synaptic Inhibition in Mouse Hippocampus

2009 ◽  
Vol 101 (3) ◽  
pp. 1179-1191 ◽  
Author(s):  
Ewa D. Zarnowska ◽  
Ruth Keist ◽  
Uwe Rudolph ◽  
Robert A. Pearce
Keyword(s):  
Cognitive Function ◽  
Small Amplitude ◽  
Drug Targets ◽  
Pyramidal Neurons ◽  
Aminobutyric Acid ◽  
Synaptic Inhibition ◽  
Wild Type ◽  
Acid Type ◽  
Mouse Hippocampus ◽  
Potential Drug Targets

γ-Aminobutyric acid type A (GABAA) receptor α5 subunits, which are heavily expressed in the hippocampus, are potential drug targets for improving cognitive function. They are found at synaptic and extrasynaptic sites and have been shown to mediate tonic inhibition in pyramidal neurons. We tested the hypothesis that α5 subunits also contribute to synaptic inhibition by measuring the effect of diazepam (DZ) on spontaneous and stimulus-evoked inhibitory postsynaptic currents (IPSCs) in genetically modified mice carrying a point mutation in the α5 subunit (α5-H105R) that renders those receptors insensitive to benzodiazepines. In wild type mice, DZ (1 μM) increased the amplitude of spontaneous IPSCs (sIPSCs) and stimulus-evoked GABAA,slow IPSCs (eIPSCs) and prolonged the decay of GABAA,fast sIPSCs. In α5-mutant mice, DZ increased the amplitude of a small-amplitude subset of sIPSCs (<50 pA) and eIPSCs (<300 pA) GABAA,slow and prolonged the decay of GABAA,fast sIPSCs, but failed to increase the amplitude of larger sIPSCs and eIPSCs GABAA,slow. These results indicate that α5 subunits contribute to a large-amplitude subset of GABAA,slow synapses and implicate these synapses in modulation of cognitive function by drugs that target α5 subunits.

The Effects of Isoflurane on Desensitized Wild-Type and ??1(S270H) ??-Aminobutyric Acid Type A Receptors

2004 ◽  
pp. 1297-1304 ◽  
Author(s):  
Adam C. Hall ◽  
Kathleen C. Rowan ◽  
Renna J. N. Stevens ◽  
Jill C. Kelley ◽  
Neil L. Harrison
Keyword(s):  
Type A ◽  
Aminobutyric Acid ◽  
Wild Type ◽  
Acid Type

Classic Benzodiazepines Modulate the Open–Close Equilibrium in α1β2γ2Lγ-Aminobutyric Acid Type A Receptors

2005 ◽  
Vol 102 (4) ◽  
pp. 783-792 ◽  
Author(s):  
Dirk Rüsch ◽  
Stuart A. Forman
Keyword(s):  
Gabaa Receptors ◽  
Sulfonic Acid ◽  
Site Occupancy ◽  
Type A ◽  
Aminobutyric Acid ◽  
Clinical Effects ◽  
Gamma Aminobutyric Acid ◽  
Wild Type ◽  
Acid Type ◽  
Benzodiazepine Site

Background Classic benzodiazepine agonists induce their clinical effects by binding to a site on gamma-aminobutyric acid type A (GABAA) receptors and enhancing receptor activity. There are conflicting data regarding whether the benzodiazepine site is allosterically coupled to gamma-aminobutyric acid binding versus the channel open-close (gating) equilibrium. The authors tested the hypothesis that benzodiazepine site ligands modulate alpha1beta2gamma2L GABAA receptor gating both in the absence of orthosteric agonists and when the orthosteric sites are occupied. Methods GABAA receptors were recombinantly expressed in Xenopus oocytes and studied using two-microelectrode voltage clamp electrophysiology. To test gating effects in the absence of orthosteric agonist, the authors used spontaneously active GABAA receptors containing a leucine-to-threonine mutation at residue 264 on the alpha1 subunit. To examine effects on gating when orthosteric sites were fully occupied, they activated wild-type receptors with high concentrations of a partial agonist, piperidine-4-sulfonic acid. Results In the absence of orthosteric agonists, the channel activity of alpha1L264Tbeta2gamma2L receptors was increased by diazepam and midazolam and reduced by the inverse benzodiazepine agonist FG7142. Flumazenil displayed very weak agonism and blocked midazolam from further activating mutant channels. In wild-type receptors activated with saturating concentrations of piperidine-4-sulfonic acid, midazolam increased maximal efficacy. Conclusions Independent of orthosteric site occupancy, classic benzodiazepines modulate the gating equilibrium in alpha1beta2gamma2L GABAA receptors and are therefore allosteric coagonists. A Monod-Wyman-Changeux coagonist gating model quantitatively predicts these effects, suggesting that benzodiazepines minimally alter orthosteric ligand binding.

Dual Actions of Enflurane on Postsynaptic Currents Abolished by the γ-Aminobutyric Acid Type A Receptor β3(N265M) Point Mutation

2006 ◽  
Vol 105 (2) ◽  
pp. 297-304 ◽  
Author(s):  
Berthold Drexler ◽  
Rachel Jurd ◽  
Uwe Rudolph ◽  
Bernd Antkowiak
Keyword(s):  
Type A ◽  
Mutant Mice ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Wild Type ◽  
Action Potential Firing ◽  
Postsynaptic Currents ◽  
Neocortical Neurons ◽  
Acid Type ◽  
Beta3 Subunit

Background At concentrations close to 1 minimum alveolar concentration (MAC)-immobility, volatile anesthetics display blocking and prolonging effects on gamma-aminobutyric acid type A receptor-mediated postsynaptic currents. It has been proposed that distinct molecular mechanisms underlie these dual actions. The authors investigated whether the blocking or the prolonging effect of enflurane is altered by a point mutation (N265M) in the beta3 subunit of the gamma-aminobutyric acid type A receptor. Furthermore, the role of the beta3 subunit in producing the depressant actions of enflurane on neocortical neurons was elucidated. Methods Spontaneous inhibitory postsynaptic currents were sampled from neocortical neurons in cultured slices derived from wild-type and beta3(N265M) mutant mice. The effects of 0.3 and 0.6 mm enflurane on decay kinetics, peak amplitude, and charge transfer were quantified. Furthermore, the impact of enflurane-induced changes in spontaneous action potential firing was evaluated by extracellular recordings in slices from wild-type and mutant mice. Results In slices derived from wild-type mice, enflurane prolonged inhibitory postsynaptic current decays and decreased peak amplitudes. Both effects were almost absent in slices from beta3(N265M) mutant mice. At clinically relevant concentrations between MAC-awake and MAC-immobility, the anesthetic was less effective in depressing spontaneous action potential firing in slices from beta3(N265M) mutant mice compared with wild-type mice. Conclusion At concentrations between MAC-awake and MAC-immobility, beta3-containing gamma-aminobutyric acid type A receptors contribute to the depressant actions of enflurane in the neocortex. The beta3(N265M) mutation affects both the prolonging and blocking effects of enflurane on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents in neocortical neurons.

γ-Aminobutyric Acid Type A Receptor β2 Subunit Mediates the Hypothermic Effect of Etomidate in Mice

2004 ◽  
Vol 100 (6) ◽  
pp. 1438-1445 ◽  
Author(s):  
Jennifer Cirone ◽  
Thomas W. Rosahl ◽  
David S. Reynolds ◽  
Richard J. Newman ◽  
Gillian F. O'Meara ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Core Body Temperature ◽  
Mutant Mice ◽  
Aminobutyric Acid ◽  
Wild Type ◽  
Acid Type ◽  
Hypothermic Response ◽  
Beta 2 ◽  
Core Body ◽  
Receptor Beta

Background The authors have previously described that the gamma-aminobutyric acid type A (GABAA) receptor beta 2N265S mutation results in a knock-in mouse with reduced sensitivity to etomidate. After recovery from etomidate anesthesia, these mice have improved motor performance and less slow wave sleep. Because most clinically used anesthetics produce hypothermia, the effect of this mutation on core body temperature was investigated. Methods The effect of etomidate and propofol on core body temperature were measured using radiotelemetry in freely moving GABAA receptor beta 2N265S mutant mice and wild-type controls. Results beta 2N265S mutant mice have a reduced hypothermic response to anesthetic doses of etomidate compared with wild-type controls and after a transient loss of righting reflex regain normothermia more rapidly compared with wild-type controls. Subanesthetic doses of etomidate produce hypothermia, which was not observed in the mutant mice. Vehicle administration resulted in a stress-induced hyperthermic response in both genotypes. Propofol produced a hypothermic response that was similar in both genotypes. Conclusions The GABAA receptor beta 2 subunit mediates a significant proportion of the hypothermic effects of etomidate. As the beta 2 subunit mediates postrecovery ataxia and sedation, anesthetic agents that do not have in vivo potency at beta 2 subunit-containing receptors offer the potential for surgical anesthesia with improved recovery characteristics.

Loss of constitutive functional γ-aminobutyric acid type A-B receptor crosstalk in layer 5 pyramidal neurons of human epileptic temporal cortex

Epilepsia ◽  
2017 ◽  
Vol 59 (2) ◽  
pp. 449-459 ◽  
Author(s):  
Katiuscia Martinello ◽  
Miriam Sciaccaluga ◽  
Roberta Morace ◽  
Addolorata Mascia ◽  
Antonietta Arcella ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Temporal Cortex ◽  
Type A ◽  
Aminobutyric Acid ◽  
Acid Type ◽  
Receptor Crosstalk

Opposing Actions of Etomidate on Cortical Theta Oscillations Are Mediated by Different γ-Aminobutyric Acid Type A Receptor Subtypes

2005 ◽  
Vol 102 (2) ◽  
pp. 346-352 ◽  
Author(s):  
Berthold Drexler ◽  
Claire L. Roether ◽  
Rachel Jurd ◽  
Uwe Rudolph ◽  
Bernd Antkowiak
Keyword(s):  
Gabaa Receptors ◽  
Type A ◽  
Mutant Mice ◽  
Theta Oscillations ◽  
Aminobutyric Acid ◽  
Receptor Subtypes ◽  
Gamma Aminobutyric Acid ◽  
Wild Type ◽  
Action Potential Firing ◽  
Acid Type

Background Cortical networks generate diverse patterns of rhythmic activity. Theta oscillations (4-12 Hz) are commonly observed during spatial learning and working memory tasks. The authors ask how etomidate, acting predominantly via gamma-aminobutyric acid type A (GABAA) receptors containing beta2 or beta3 subunits, affects theta activity in vitro. Methods To characterize the effects of etomidate, the authors recorded action potential firing together with local field potentials in slice cultures prepared from the neocortex of the beta3(N265M) knock-in mutant and wild type mice. Actions of etomidate were studied at 0.2 microm, which is approximately 15% of the concentration causing immobility ( approximately 1.5 microm). Results In preparations derived from wild type and beta3(N265M) mutant mice, episodes of ongoing activity spontaneously occurred at a frequency of approximately 0.1 Hz and persisted for several seconds. Towards the end of these periods, synchronized oscillations in the theta band developed. These oscillations were significantly depressed in slices from beta3(N265M) mutant mice (P &lt; 0.05). In this preparation etomidate acts almost exclusively via beta2 subunit containing GABAA receptors. In contrast, no depression was observed in slices from wild type mice, where etomidate potentiates both beta2- and beta3-containing GABAA receptors. Conclusions At concentrations assumed to cause sedation and amnesia, etomidate depresses theta oscillations via beta2-containing GABAA receptors but enhances these oscillations by acting on beta3 subunit containing receptors. This indicates that the overall effect of the anesthetic reflects a balance between enhancement and inhibition produced by different GABAA receptor subtypes.

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