scholarly journals Zolpidem Activation of Alpha 1-Containing GABAA Receptors Selectively Inhibits High Frequency Action Potential Firing of Cortical Neurons

2019 ◽  
Vol 9 ◽  
Author(s):  
Elena Neumann ◽  
Uwe Rudolph ◽  
Daniel E. Knutson ◽  
Guanguan Li ◽  
James M. Cook ◽  
...  
Keyword(s):  
Action Potential ◽  
Gabaa Receptors ◽  
High Frequency ◽  
Cortical Neurons ◽  
Action Potential Firing ◽  
Potential Firing

Propofol and Sevoflurane Depress Spinal Neurons In Vitro via  Different Molecular Targets

2004 ◽  
Vol 101 (5) ◽  
pp. 1167-1176 ◽  
Author(s):  
Christian Grasshoff ◽  
Bernd Antkowiak
Keyword(s):  
Spinal Cord ◽  
Action Potential ◽  
Gabaa Receptors ◽  
Molecular Targets ◽  
Glycine Receptors ◽  
Spinal Neurons ◽  
Action Potential Firing ◽  
Spontaneous Action Potential ◽  
Potential Firing ◽  
Spontaneous Action

Background The capacity of general anesthetics to produce immobility is primarily spinally mediated. Recently, compelling evidence has been provided that the spinal actions of propofol involve gamma-aminobutyric acid type A (GABAA) receptors, whereas the contribution of glycine receptors remains uncertain. The relevant molecular targets of the commonly used volatile anesthetic sevoflurane in the spinal cord are largely unknown, but indirect evidence suggests a mechanism of action distinct from propofol. Methods The effects of sevoflurane and propofol on spontaneous action potential firing were investigated by extracellular voltage recordings from ventral horn interneurons in cultured spinal cord tissue slices obtained from embryonic rats (embryonic days 14-15). Results Propofol and sevoflurane reduced spontaneous action potential firing of neurons. Concentrations causing half-maximal effects (0.11 microm propofol, 0.11 mm sevoflurane) were lower than the median effective concentration immobility (1-1.5 microm propofol, 0.35 mm sevoflurane). At higher concentrations, complete inhibition of action potential activity was observed with sevoflurane but not with propofol. Effects of sevoflurane were mediated predominantly by glycine receptors (45%) and GABAA receptors (38%), whereas propofol acted almost exclusively via GABAA receptors (96%). Conclusions The authors' results suggest that glycine and GABAA receptors are the most important molecular targets mediating depressant effects of sevoflurane in the spinal cord. They provide evidence that sevoflurane causes immobility by a mechanism distinct from the actions of the intravenous anesthetic propofol. The finding that propofol acts exclusively via GABAA receptors can explain its limited capacity to depress spinal neurons in the authors' study.

scholarly journals Diazepam and ethanol differently modulate neuronal activity in organotypic cortical cultures

2019 ◽  
Author(s):  
Matthias Kreuzer ◽  
Paul S García ◽  
Verena Brucklacher-Waldert ◽  
Rebecca Claasen ◽  
Gerhard Schneider ◽  
...  
Keyword(s):  
Action Potential ◽  
Gabaa Receptors ◽  
Cortical Neurons ◽  
Spectral Power ◽  
Spectral Composition ◽  
Field Potential ◽  
Cortical Network ◽  
Ethanol Administration ◽  
Action Potential Firing ◽  
Experimental Conditions

Abstract Background: The pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic, sedative-hypnotic effects. Although each of these molecules effectively reduce the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABAA receptors containing a g-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons. Method: We used electrophysiological recordings from organotypic slice cultures derived from Sprague-Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM, n = 7) or ethanol (30 and 60 mM, n = 11) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase. Results: While both substances seem to decrease neocortical action potential firing in a not significantly different (p=0.659, Mann-Whitney U) fashion, diazepam increases the spectral power of the up-state without significantly impacting the spectral composition, whereas ethanol does not significantly change the spectral power but the oscillatory architecture of the up-state as revealed by the Friedman test with Bonferroni correction (p<0.05). Further, the action potential to LFP-phase coupling reveals a synchronizing effect of diazepam for a wide frequency range and a narrow-band de-synchronizing effect for ethanol (p<0.05, Kolmogorov-Smirnov test). Conclusion: Diazepam and ethanol, induce specific patterns of network depressant actions. Diazepam induces cortical network inhibition and increased synchronicity via gamma subunit containing GABAA receptors. Ethanol also induces cortical network inhibition, but without an increase in synchronicity via a wider span of molecular targets.

scholarly journals Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor Networks

2020 ◽  
Vol 21 (19) ◽  
pp. 7399
Author(s):  
Berthold Drexler ◽  
Julia Grenz ◽  
Christian Grasshoff ◽  
Bernd Antkowiak
Keyword(s):  
Action Potential ◽  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Cell Voltage ◽  
Gabaergic Inhibition ◽  
Action Potential Firing ◽  
Spinal Interneurons ◽  
Combined Application ◽  
Spinal Motor ◽  
Potential Firing

The neurosteroid allopregnanolone (ALLO) causes unconsciousness by allosteric modulation of γ-aminobutyric acid type A (GABAA) receptors, but its actions on the spinal motor networks are unknown. We are therefore testing the hypothesis that ALLO attenuates the action potential firing of spinal interneurons and motoneurons predominantly via enhancing tonic, but not synaptic GABAergic inhibition. We used video microscopy to assess motoneuron-evoked muscle activity in organotypic slice cultures prepared from the spinal cord and muscle tissue. Furthermore, we monitored GABAA receptor-mediated currents by performing whole-cell voltage-clamp recordings. We found that ALLO (100 nM) reduced the action potential firing of spinal interneurons by 27% and that of α-motoneurons by 33%. The inhibitory effects of the combination of propofol (1 µM) and ALLO on motoneuron-induced muscle contractions were additive. Moreover, ALLO evoked a tonic, GABAA receptor-mediated current (amplitude: 41 pA), without increasing phasic GABAergic transmission. Since we previously showed that at a clinically relevant concentration of 1 µM propofol enhanced phasic, but not tonic GABAergic inhibition, we conclude that ALLO and propofol target distinct subpopulations of GABAA receptors. These findings provide first evidence that the combined application of ALLO and propofol may help to reduce intraoperative movements and undesired side effects that are frequently observed under total intravenous anesthesia.

scholarly journals Spike-frequency dependent inhibition and excitation of neural activity by high-frequency ultrasound

2020 ◽  
Author(s):  
Martin Loynaz Prieto ◽  
Kamyar Firouzi ◽  
Butrus T. Khuri-Yakub ◽  
Daniel V. Madison ◽  
Merritt Maduke
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
High Frequency ◽  
Pyramidal Neurons ◽  
Potassium Conductance ◽  
Firing Frequency ◽  
Resting Membrane Potential ◽  
Action Potential Firing ◽  
Voltage Dependent ◽  
Potential Firing

ABSTRACTUltrasound can modulate action-potential firing in vivo and in vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we used patch-clamp recording to quantify the effects of focused, high-frequency (43 MHz) ultrasound on evoked action potential firing in CA1 pyramidal neurons in acute rodent hippocampal brain slices. We find that ultrasound can either inhibit or potentiate firing in a spike-frequency-dependent manner: at low (near-threshold) input currents and low firing frequencies, ultrasound inhibits firing, while at higher input currents and higher firing frequencies, ultrasound potentiates firing. The net result of these two competing effects is that ultrasound increases the threshold current for action potential firing, the slope of frequency-input curves, and the maximum firing frequency. In addition, ultrasound slightly hyperpolarizes the resting membrane potential, decreases action potential width, and increases the depth of the afterhyperpolarization. All of these results can be explained by the hypothesis that ultrasound activates a sustained potassium conductance. According to this hypothesis, increased outward potassium currents hyperpolarize the resting membrane potential and inhibit firing at near-threshold input currents, but potentiate firing in response to higher input currents by limiting inactivation of voltage-dependent sodium channels during the action potential. This latter effect is a consequence of faster action-potential repolarization, which limits inactivation of voltage-dependent sodium channels, and deeper (more negative) afterhyperpolarization, which increases the rate of recovery from inactivation. Based on these results we propose that ultrasound activates thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels, through heating or mechanical effects of acoustic radiation force. Finite-element modelling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (less than 2°C) increase in temperature, with possible additional contributions from mechanical effectsSUMMARYPrieto et al. describe how ultrasound can either inhibit or potentiate action potential firing in hippocampal pyramidal neurons and demonstrate that these effects can be explained by increased potassium conductance.

scholarly journals Spike frequency–dependent inhibition and excitation of neural activity by high-frequency ultrasound

2020 ◽  
Vol 152 (11) ◽  
Author(s):  
Martin Loynaz Prieto ◽  
Kamyar Firouzi ◽  
Butrus T. Khuri-Yakub ◽  
Daniel V. Madison ◽  
Merritt Maduke
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Sodium Channels ◽  
High Frequency ◽  
Firing Frequency ◽  
Resting Membrane Potential ◽  
Action Potential Firing ◽  
Mechanical Effects ◽  
Voltage Dependent ◽  
Potential Firing

Ultrasound can modulate action potential firing in vivo and in vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we used patch-clamp recording to quantify the effects of focused, high-frequency (43 MHz) ultrasound on evoked action potential firing in CA1 pyramidal neurons in acute rodent hippocampal brain slices. We find that ultrasound can either inhibit or potentiate firing in a spike frequency–dependent manner: at low (near-threshold) input currents and low firing frequencies, ultrasound inhibits firing, while at higher input currents and higher firing frequencies, ultrasound potentiates firing. The net result of these two competing effects is that ultrasound increases the threshold current for action potential firing, the slope of frequency-input curves, and the maximum firing frequency. In addition, ultrasound slightly hyperpolarizes the resting membrane potential, decreases action potential width, and increases the depth of the after-hyperpolarization. All of these results can be explained by the hypothesis that ultrasound activates a sustained potassium conductance. According to this hypothesis, increased outward potassium currents hyperpolarize the resting membrane potential and inhibit firing at near-threshold input currents but potentiate firing in response to higher-input currents by limiting inactivation of voltage-dependent sodium channels during the action potential. This latter effect is a consequence of faster action potential repolarization, which limits inactivation of voltage-dependent sodium channels, and deeper (more negative) after-hyperpolarization, which increases the rate of recovery from inactivation. Based on these results, we propose that ultrasound activates thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels through heating or mechanical effects of acoustic radiation force. Finite-element modeling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (&lt;2°C) increase in temperature, with possible additional contributions from mechanical effects.

scholarly journals Cholinergic Modulation of Sevoflurane Potency in Cortical and Spinal Networks In Vitro 

2007 ◽  
Vol 106 (6) ◽  
pp. 1147-1155 ◽  
Author(s):  
Christian Grasshoff ◽  
Berthold Drexler ◽  
Harald Hentschke ◽  
Horst Thiermann ◽  
Bernd Antkowiak
Keyword(s):  
Action Potential ◽  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Receptor Function ◽  
Action Potential Firing ◽  
Newborn Mice ◽  
Organophosphate Intoxication ◽  
Spontaneous Action Potential ◽  
Potential Firing ◽  
Spontaneous Action

Background Victims of organophosphate intoxication with cholinergic crisis may have need for sedation and anesthesia, but little is known about how anesthetics work in these patients. Recent studies suggest that cholinergic stimulation impairs gamma-aminobutyric acid type A (GABAA) receptor function. Because GABAA receptors are major targets of general anesthetics, the authors investigated interactions between acetylcholine and sevoflurane in spinal and cortical networks. Methods Cultured spinal and cortical tissue slices were obtained from embryonic and newborn mice. Drug effects were assessed by extracellular voltage recordings of spontaneous action potential activity. Results Sevoflurane caused a concentration-dependent decrease in spontaneous action potential firing in spinal (EC50=0.17+/-0.02 mM) and cortical (EC50=0.29+/-0.01 mM) slices. Acetylcholine elevated neuronal excitation in both preparations and diminished the potency of sevoflurane in reducing action potential firing in cortical but not in spinal slices. This brain region-specific decrease in sevoflurane potency was mimicked by the specific GABAA receptor antagonist bicuculline, suggesting that (1) GABAA receptors are major molecular targets for sevoflurane in the cortex but not in the spinal cord and (2) acetylcholine impairs the efficacy of GABAA receptor-mediated inhibition. The latter hypothesis was supported by the finding that acetylcholine reduced the potency of etomidate in depressing cortical and spinal neurons. Conclusions The authors raise the question whether cholinergic overstimulation decreases the efficacy of GABAA receptor function in patients with organophosphate intoxication, thereby compromising anesthetic effects that are mediated predominantly via these receptors such as sedation and hypnosis.

scholarly journals Enhancing the function of alpha5-subunit-containing GABAA receptors promotes action potential firing of neocortical neurons during up-states

2013 ◽  
Vol 703 (1-3) ◽  
pp. 18-24 ◽  
Author(s):  
Berthold Drexler ◽  
Stefan Zinser ◽  
Shengming Huang ◽  
Michael M. Poe ◽  
Uwe Rudolph ◽  
...  
Keyword(s):  
Action Potential ◽  
Gabaa Receptors ◽  
Action Potential Firing ◽  
Neocortical Neurons ◽  
Up States ◽  
Potential Firing

scholarly journals Diazepam and ethanol differently modulate neuronal activity in organotypic cortical cultures

2019 ◽  
Author(s):  
Matthias Kreuzer ◽  
Paul S García ◽  
Verena Brucklacher-Waldert ◽  
Rebecca Claasen ◽  
Gerhard Schneider ◽  
...  
Keyword(s):  
Action Potential ◽  
Gabaa Receptors ◽  
Cortical Neurons ◽  
Spectral Power ◽  
Spectral Composition ◽  
Field Potential ◽  
Cortical Network ◽  
Ethanol Administration ◽  
Action Potential Firing ◽  
Experimental Conditions

Abstract Background: The pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic, sedative-hypnotic effects. Although each of these molecules effectively reduce the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABAA receptors containing a g-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons. Method: We used electrophysiological recordings from organotypic slice cultures derived from Sprague-Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM, n = 7) or ethanol (30 and 60 mM, n = 11) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase. Results: While both substances seem to decrease neocortical action potential firing in a not significantly different (p=0.659, Mann-Whitney U) fashion, diazepam increases the spectral power of the up-state without significantly impacting the spectral composition, whereas ethanol does not significantly change the spectral power but the oscillatory architecture of the up-state as revealed by the Friedman test with Bonferroni correction (p<0.05). Further, the action potential to LFP-phase coupling reveals a synchronizing effect of diazepam for a wide frequency range and a narrow-band de-synchronizing effect for ethanol (p<0.05, Kolmogorov-Smirnov test). Conclusion: Diazepam and ethanol, induce specific patterns of network depressant actions. Diazepam induces cortical network inhibition and increased synchronicity via gamma subunit containing GABAA receptors. Ethanol also induces cortical network inhibition, but without an increase in synchronicity via a wider span of molecular targets.

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