In vitro networks: cortical mechanisms of anaesthetic action

Antkowiak, Bernd

doi:10.1093/bja/aef154

Cited by 57 publications

(44 citation statements)

References 74 publications

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“…This view is fostered by invitro experiments on cortical slices while applying anesthetic agents. Such experiments showed that the firing rates of neurons decreased during the administration of an increased concentration of the AA (Antkowiak 1999(Antkowiak , 2002 similar to neural effects observed in invivo experiments. These findings indicate that anesthetic effects may occur in a single brain area and network interactions might not be necessary for their occurrence.…”

Section: Introductionsupporting

confidence: 66%

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Effects of the anesthetic agent propofol on neural populations

Hutt

Longtin

2009

Cogn Neurodyn

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The neuronal mechanisms of general anesthesia are still poorly understood. Besides several characteristic features of anesthesia observed in experiments, a prominent effect is the bi-phasic change of power in the observed electroencephalogram (EEG), i.e. the initial increase and subsequent decrease of the EEG-power in several frequency bands while increasing the concentration of the anaesthetic agent. The present work aims to derive analytical conditions for this bi-phasic spectral behavior by the study of a neural population model. This model describes mathematically the effective membrane potential and involves excitatory and inhibitory synapses, excitatory and inhibitory cells, nonlocal spatial interactions and a finite axonal conduction speed. The work derives conditions for synaptic time constants based on experimental results and gives conditions on the resting state stability. Further the power spectrum of Local Field Potentials and EEG generated by the neural activity is derived analytically and allow for the detailed study of bi-spectral power changes. We find bi-phasic power changes both in monostable and bistable system regime, affirming the omnipresence of bi-spectral power changes in anesthesia. Further the work gives conditions for the strong increase of power in the d-frequency band for large propofol concentrations as observed in experiments.

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Section: Introductionsupporting

confidence: 66%

“…The resting EEG power spectrum especially reflects the anesthetic action in a characteristic way and permits the classification of the depth of anesthesia by so-called monitors, see e.g. the review of Antkowiak (2002). These monitors are also used to pinpoint the LOC.…”

Section: Introductionmentioning

confidence: 99%

Effects of the anesthetic agent propofol on neural populations

Hutt

Longtin

2009

Cogn Neurodyn

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“…Together, these data demonstrate that halothane modulation of native neuronal I h is represented by more prominent gating effects in channels that include HCN1 subunits and relatively greater amplitude inhibition in channels that include HCN2 subunits; by interacting with C-terminal domains, cAMP pushes HCN2 channels into a state of lower basal inhibition (i.e., more depolarized V 1/2 ) in which actions of halothane are characterized by larger shifts in V 1/2 and smaller decreases in maximal available current (i.e., more HCN1-like). The strong inhibition of HCN channels by halothane at concentrations obtained during general anesthesia (Franks and Lieb, 1994;Eckenhoff and Johansson, 1999), together with the recognized role of I h in CNS functions that are affected by general anesthesia (e.g., thalamocortical rhythms) (Steriade et al, 1993;McCormick and Bal, 1997;Alkire et al, 2000;Antkowiak, 2002;Harrison, 2002;Campagna et al, 2003), suggest that I h modulation may contribute to clinical actions of these important drugs.…”

Section: Discussionmentioning

confidence: 99%

HCN Subunit-Specific and cAMP-Modulated Effects of Anesthetics on Neuronal Pacemaker Currents

Chen

Sirois²,

Lei³

et al. 2005

Journal of Neuroscience

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General anesthetics have been a mainstay of surgical practice for more than 150 years, but the mechanisms by which they mediate their important clinical actions remain unclear. Ion channels represent important anesthetic targets, and, although GABA A receptors have emerged as major contributors to sedative, immobilizing, and hypnotic effects of intravenous anesthetics, a role for those receptors is less certain in the case of inhalational anesthetics. The neuronal hyperpolarization-activated pacemaker current (I h ) is essential for oscillatory and integrative properties in numerous cell types. Here, we show that clinically relevant concentrations of inhalational anesthetics modulate neuronal I h and the corresponding HCN channels in a subunit-specific and cAMP-dependent manner. Anesthetic inhibition of I h involves a hyperpolarizing shift in voltage dependence of activation and a decrease in maximal current amplitude; these effects can be ascribed to HCN1 and HCN2 subunits, respectively, and both actions are recapitulated in heteromeric HCN1-HCN2 channels. Mutagenesis and simulations suggest that apparently distinct actions of anesthetics on V 1/2 and amplitude represent different manifestations of a single underlying mechanism (i.e., stabilization of channel closed state), with the predominant action determined by basal inhibition imposed by individual subunit C-terminal domains and relieved by cAMP. These data reveal a molecular basis for multiple actions of anesthetics on neuronal HCN channels, highlight the importance of proximal C terminus in modulation of HCN channel gating by diverse agents, and advance neuronal pacemaker channels as potentially relevant targets for clinical actions of inhaled anesthetics.

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“…Our results verify HCN subunit-specific effects of isoflurane and demonstrate that inhibition of I h by isoflurane causes membrane hyperpolarization and enhanced synaptic summation; the net effect of these changes in cortical neuronal properties is an increase in synaptic excitability. Thus isoflurane-mediated inhibition of HCN1-containing channels may contribute to synaptically driven slow-wave oscillations in thalamocortical circuits (McCormick and Bal 1997;Rudolph and Antkowiak 2004;Steriade et al 1993a), such as those associated with hypnosis at the onset of anesthesia (Antkowiak 2002).…”

Section: Introductionmentioning

confidence: 99%

Subunit-Specific Effects of Isoflurane on Neuronal I_h in HCN1 Knockout Mice

Chen¹,

Shu²,

Kennedy³

et al. 2009

Journal of Neurophysiology

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Chen X, Shu S, Kennedy DP, Willcox SC, Bayliss DA. Subunitspecific effects of isoflurane on neuronal I h in HCN1 knockout mice. J Neurophysiol 101: 129 -140, 2009. First published October 29, 2008 doi:10.1152/jn.01352.2007. The ionic mechanisms that contribute to general anesthetic actions have not been elucidated, although increasing evidence has pointed to roles for subthreshold ion channels, such as the HCN channels underlying the neuronal hyperpolarizationactivated cationic current (I h ). Here, we used conventional HCN1 knockout mice to test directly the contributions of specific HCN subunits to effects of isoflurane, an inhalational anesthetic, on membrane and integrative properties of motor and cortical pyramidal neurons in vitro. Compared with wild-type mice, residual I h from knockout animals was smaller in amplitude and presented with HCN2-like properties. Inhibition of I h by isoflurane previously attributed to HCN1 subunit-containing channels (i.e., a hyperpolarizing shift in half-activation voltage [V 1/2 ]) was absent in neurons from HCN1 knockout animals; the remaining inhibition of current amplitude could be attributed to effects on residual HCN2 channels. We also found that isoflurane increased temporal summation of excitatory postsynaptic potentials (EPSPs) in cortical neurons from wild-type mice; this effect was predicted by simulation of anesthetic-induced dendritic I h inhibition, which also revealed more prominent summation accompanying shifts in V 1/2 (an HCN1-like effect) than decreased current amplitude (an HCN2-like effect). Accordingly, anestheticinduced EPSP summation was not observed in cortical cells from HCN1 knockout mice. In wild-type mice, the enhanced synaptic summation observed with low concentrations of isoflurane contributed to a net increase in cortical neuron excitability. In summary, HCN channel subunits account for distinct anesthetic effects on neuronal membrane properties and synaptic integration; inhibition of HCN1 in cortical neurons may contribute to the synaptically mediated slow-wave cortical synchronization that accompanies anesthetic-induced hypnosis.

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In vitro networks: cortical mechanisms of anaesthetic action

Cited by 57 publications

References 74 publications

Effects of the anesthetic agent propofol on neural populations

Effects of the anesthetic agent propofol on neural populations

HCN Subunit-Specific and cAMP-Modulated Effects of Anesthetics on Neuronal Pacemaker Currents

Subunit-Specific Effects of Isoflurane on Neuronal I_h in HCN1 Knockout Mice

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In vitro networks: cortical mechanisms of anaesthetic action

Cited by 57 publications

References 74 publications

Effects of the anesthetic agent propofol on neural populations

Effects of the anesthetic agent propofol on neural populations

HCN Subunit-Specific and cAMP-Modulated Effects of Anesthetics on Neuronal Pacemaker Currents

Subunit-Specific Effects of Isoflurane on Neuronal Ih in HCN1 Knockout Mice

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Subunit-Specific Effects of Isoflurane on Neuronal I_h in HCN1 Knockout Mice