Voltage-clamp analysis of halothane effects on GABAAfast and GABAAslow inhibitory currents

Lukatch, Heath S.; MacIver, M Bruce

doi:10.1016/s0006-8993(97)00516-7

Cited by 22 publications

(11 citation statements)

References 14 publications

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“…However, even if these drugs do modulate the same receptors or synapses, and even if these actions do contribute to their amnestic properties, different classes of drugs might achieve amnesia by way of quantitatively different balances of effects on IPSCs vs. other targets – or even via qualitatively different types of effects on IPSCs. For example, whereas we found that the major effect of etomidate was to slow GABAA, slow IPSC decay, benzodiazepines were shown recently to increase GABAA, slow amplitude rather than decay,9 and halothane modulated GABAA, fast and GABAA, slow currents similarly, altering decay but not amplitude 33…”

Section: Discussionmentioning

confidence: 57%

Amnestic Concentrations of Etomidate Modulate GABAA,slowSynaptic Inhibition in Hippocampus

Dai¹,

Perouansky

Pearce

2009

Anesthesiology

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Background γ-aminobutyric acid type A (GABAA) receptor-mediated inhibition in the central nervous system exists in two forms: phasic (inhibitory postsynaptic currents, IPSCs) and tonic (non-synaptic). Phasic inhibition is further subdivided into fast (GABAA, fast) and slow (GABAA, slow) IPSCs. By virtue of its dendritic location and kinetics, GABAA, slow has been proposed to control synaptic plasticity and memory. Etomidate is a non-barbiturate, intravenous anesthetic that selectively modulates GABAA receptors and produces amnesia at low doses in vivo. Here we have tested whether correspondingly low concentrations of etomidate in vitro alter GABAA, fast and GABAA, slow phasic inhibition. Methods Electrophysiological recordings were obtained from hippocampal slices prepared from postnatal day 3–8 mice and maintained in organotypic culture for 10–14 days. Etomidate was applied at concentrations corresponding to one-half to four times the half maximal effective concentration that impairs hippocampus-dependent learning and memory – i.e. 0.125 to 1 μM. Results Etomidate 0.25 μM (the half maximal effective concentration) doubled the time constant of decay of GABAA, slow IPSCs but had no detectable effect on GABAA, fast IPSCs. Higher concentrations of etomidate had stronger effects on both types of phasic inhibition: 0.5 and 1 μM etomidate prolonged the time constant of decay by 310% and 410% for GABAA, slow and by 25% and 78% for GABAA, fast. Concentrations of etomidate up to 1 μM had no significant effects on the amplitudes of either GABAA, fast or GABAA, slow IPSCs. Conclusions At concentrations that impair hippocampus-dependent memory, etomidate modulates GABAA, slow more strongly than GABAA, fast IPSCs. Effects of etomidate on GABAA, slow IPSCs may contribute to etomidate-induced amnesia.

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Section: Discussionmentioning

confidence: 57%

Amnestic Concentrations of Etomidate Modulate GABAA,slowSynaptic Inhibition in Hippocampus

Dai¹,

Perouansky

Pearce

2009

Anesthesiology

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“…reported: GABA Afast and GABA Aslow (Pearce, 1993). It has also been shown that halothane (1.2 vol%) prolonged the decay of these two types of IPSCs similarly (ϳ2.5-fold), with minimal changes in IPSC amplitudes and rise times (Lukatch and MacIver, 1997). SL-M-SR border stimuli-evoked IPSCs recorded from pyramidal cells ( Fig.…”

Section: Halothane Effects On Stimulus-evoked Ipscs Recorded From Pyrmentioning

confidence: 72%

“…The finding that anesthetics enhance synaptic inhibition was first demonstrated by Nicoll (1972), who showed that pentobarbital prolonged the time course of IPSPs. Many studies have confirmed that anesthetics prolong the decay phase of GABA A receptormediated synaptic currents in dissociated cultured neurons (Nakahiro et al, 1989;Jones et al, 1992;Jones and Harrison, 1993) and in CA1 pyramidal neurons in vivo and in brain slices (Nicoll et al, 1975;Lukatch and MacIver, 1997;Banks and Pearce, 1999). GABA A receptors have modulatory binding sites for benzodiazepines, barbiturates, and anesthetics, all of which potentiate responses to GABA (for review, see Tanelian et al, 1993;Mac-Donald and Olsen, 1994).…”

mentioning

confidence: 94%

Membrane and Synaptic Actions of Halothane on Rat Hippocampal Pyramidal Neurons and Inhibitory Interneurons

Nishikawa

MacIver

2000

J. Neurosci.

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A relatively small number of inhibitory interneurons can control the excitability and synchronization of large numbers of pyramidal neurons in hippocampus and other cortical regions. Thus, anesthetic modulation of interneurons could play an important role during anesthesia. The aim of this study was to investigate effects of a general anesthetic, halothane, on membrane and synaptic properties of rat hippocampal interneurons. GABA receptor-mediated IPSCs were recorded with whole-cell patch-clamp techniques in visually identified CA1 pyramidal cells and interneurons located at the border of stratum lacunosum-moleculare and stratum radiatum. Halothane (0.35 mm congruent with 1.2 vol%) depressed evoked IPSC amplitudes recorded from both pyramidal cells and inhibitory interneurons. Also, halothane considerably prolonged the decay time constant of evoked IPSCs in pyramidal cells and interneurons. The frequencies of miniature IPSCs were increased by halothane (two- to threefold) in both types of neuron. On the other hand, halothane effects on resting membrane potentials were variable but minimal in both types of neurons. In current-clamp recordings, halothane depressed EPSP amplitudes and increased IPSP amplitudes recorded from both types of neurons. In addition, halothane increased the failure rate of synaptically evoked action potentials. Taken together, these data provide evidence that halothane increases GABA(A) receptor-mediated synaptic inhibition between synaptically connected interneurons and depresses excitatory transmission, similar to effects observed in pyramidal neurons.

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“…Several studies provided evidence that the time course of GABAergic currents shows a substantial voltage-dependence (Barker and Harrison, 1988; Weiss et al, 1988; Jones and Harrison, 1993; Pearce, 1993; Lukatch and MacIver, 1997; Mellor and Randall, 1998; Krishek and Smart, 2001). Since the mechanisms underlying the modulation of GABAergic currents by voltage have not been fully elucidated, we have performed a kinetic analysis of current responses evoked by rapid applications of exogenous GABA (Pytel et al, 2006).…”

Section: Consideration Of Synaptic Agonist Transient Sheds New Light mentioning

confidence: 99%

Impact of Synaptic Neurotransmitter Concentration Time Course on the Kinetics and Pharmacological Modulation of Inhibitory Synaptic Currents

Barberis¹,

Petrini²,

Mozrzymas³

2011

Front. Cell. Neurosci.

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The time course of synaptic currents is a crucial determinant of rapid signaling between neurons. Traditionally, the mechanisms underlying the shape of synaptic signals are classified as pre- and post-synaptic. Over the last two decades, an extensive body of evidence indicated that synaptic signals are critically shaped by the neurotransmitter time course which encompasses several phenomena including pre- and post-synaptic ones. The agonist transient depends on neurotransmitter release mechanisms, diffusion within the synaptic cleft, spill-over to the extra-synaptic space, uptake, and binding to post-synaptic receptors. Most estimates indicate that the neurotransmitter transient is very brief, lasting between one hundred up to several hundreds of microseconds, implying that post-synaptic activation is characterized by a high degree of non-equilibrium. Moreover, pharmacological studies provide evidence that the kinetics of agonist transient plays a crucial role in setting the susceptibility of synaptic currents to modulation by a variety of compounds of physiological or clinical relevance. More recently, the role of the neurotransmitter time course has been emphasized by studies carried out on brain slice models that revealed a striking, cell-dependent variability of synaptic agonist waveforms ranging from rapid pulses to slow volume transmission. In the present paper we review the advances on studies addressing the impact of synaptic neurotransmitter transient on kinetics and pharmacological modulation of synaptic currents at inhibitory synapses.

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Voltage-clamp analysis of halothane effects on GABAAfast and GABAAslow inhibitory currents

Cited by 22 publications

References 14 publications

Amnestic Concentrations of Etomidate Modulate GABAA,slowSynaptic Inhibition in Hippocampus

Amnestic Concentrations of Etomidate Modulate GABAA,slowSynaptic Inhibition in Hippocampus

Membrane and Synaptic Actions of Halothane on Rat Hippocampal Pyramidal Neurons and Inhibitory Interneurons

Impact of Synaptic Neurotransmitter Concentration Time Course on the Kinetics and Pharmacological Modulation of Inhibitory Synaptic Currents

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