Attenuation of Native Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Volatile Anesthetic Sevoflurane in Mouse Thalamocortical Relay Neurons

Schwerin, Stefan; Kopp, Claudia; Pircher, Elisabeth; Schneider, Gerhard; Kreuzer, Matthias; Haseneder, Rainer; Kratzer, Stephan

doi:10.3389/fncel.2020.606687

Cited by 6 publications

(6 citation statements)

References 76 publications

(149 reference statements)

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“…Our findings suggest that cGMP/HCN signaling partially mediates volatile anesthetic actions on presynaptic function in hippocampal neurons. Previous studies have implicated HCN in anesthetic mechanisms in thalamic 34 , thalamocortical 35 , and forebrain neurons 36 . HCN channels can be gated by either cAMP or cGMP; our study is the first to link volatile anesthetic depression of cGMP production with reduced HCN function.…”

Section: Discussionmentioning

confidence: 99%

Volatile anesthetics inhibit presynaptic cGMP signaling to depress presynaptic excitability in rat hippocampal neurons

Speigel

Osman

Hemmings

2022

Preprint

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Volatile anesthetics alter presynaptic function including effects on Ca2+ influx and neurotransmitter release. These actions are proposed to play important roles in their pleiotropic neurophysiological effects including unconsciousness and amnesia. The nitric oxide and cyclic guanosine monophosphate (NO/cGMP) signaling pathway has been implicated in presynaptic mechanisms, and disruption of NO/cGMP signaling has been shown to alter sensitivity to volatile anesthetics in vivo. We investigated NO/cGMP signaling in relation to volatile anesthetic actions in cultured rat hippocampal neurons using pharmacological tools and genetically encoded biosensors of cGMP levels. Using the fluorescent biosensor cGull we found that electrical stmulation-evoked NMDA-type glutamate receptor-independent presynaptic cGMP transients were inhibited -33.2% by isoflurane (0.51 mM) and -23.8% by sevoflurane (0.57 mM) (p<0.0001) compared to a stimulation without anesthetic. Isoflurane and sevoflurane inhibition of stimulation-evoked increases in presynaptic Ca2+ concentration, measured with synaptophysin-GCaMP6f, and synaptic vesicle exocytosis, measured with synaptophysin-pHlourin, were reduced by in neurons expressing the cGMP scavenger sponGee. This reduction in anesthetic effect was recapitulated by inhibiting HCN channels, a cGMP-modulated effector that can facilitate glutamate release. We propose that volatile anesthetics depress presynaptic cGMP signaling and downstream effectors like HCN channels that are essential to presynaptic function and excitability. These findings identify a novel mechanism by which volatile anesthetics depress synaptic transmission via second messenger signaling involving the NO/cGMP pathway.

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Section: Discussionmentioning

confidence: 99%

Volatile anesthetics inhibit presynaptic cGMP signaling to depress presynaptic excitability in rat hippocampal neurons

Speigel

Osman

Hemmings

2022

Preprint

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“…Sevoflurane, as a common inhalation anesthetic, is widely used in the field of anesthesiology over the world. HCN channels as the target for sevoflurane were sufficiently established by our team and other researchers [ 18 , 19 ]. To the best of our knowledge, this study was the first report to demonstrate that sevoflurane acts on its target-HCN2 channel to regulate microglial function and neuroinflammation in vivo, triggering cognitive impairment and anxiety-like behaviors in rats.…”

Section: Discussionmentioning

confidence: 99%

“…We and others found that sevoflurane, as a volatile anesthetic, can inhibit hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, and HCN knockout or selective HCN channel blocker ZD7288 can increase anesthetic properties of sevoflurane [ 18 , 19 ]. Interestingly, an in vitro experiment has provided the novel discovery that HCN channels can be expressed on primary microglia and contribute to various microglial functions and influence the course of microglial activation [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

PEX5R/Trip8b-HCN2 channel regulating neuroinflammation involved in perioperative neurocognitive disorders

Wang

Han

et al. 2022

Cell Biosci

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Background Clinical and animal studies demonstrated that neuroinflammation from anesthesia (sevoflurane) is the main contributor to cause perioperative neurocognitive disorders (PND). Recently, it was reported that microglia respond to hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which was the target of sevoflurane. Whether HCN channels are involved in the induction of neuroinflammation after sevoflurane exposure is still unclear. Results Sevoflurane exposure had increased cognitive dysfunction and anxiety-like behaviors in rats. Rats inhaled with sevoflurane had activated microglia and increased neuroinflammation (IL-1β, IL-6, and TNF-α) in the hippocampus. RNA sequencing identified 132 DEGs (86 up-regulated and 46 down-regulated DEGs [differentially expressed genes]) in the hippocampus of PND rats. RNA-sequencing also uncovered that sevoflurane exposure down-regulates HCN2 expression. Pathway and process enrichment analysis suggests DEGs are mainly enriched in regulation of system process, positive regulation of glutamate secretion, secretion, regulation of synaptic transmission, regulation of nervous system process, behavior, negative regulation of sodium ion transport, and learning or memory. We validated that sevoflurane exposure can down-regulate the levels of PEX5R/Trip8b (an interaction partner and auxiliary subunit of HCN channels) and HCN1-4 channels in the hippocampus of PND rats. We used immunofluorescence staining to identify that HCN2 co-labels with neurons (Neun), astrocytes (GFAP), and microglia (iba1). We observed that the co-labeling of HCN2 with neurons or microglia decreased in the hippocampus and cortex after sevoflurane exposure. Blocking HCN2 by ZD7288 treatment further activated microglia and aggravated sevoflurane exposure-induced anxiety-like behavior, cognitive impairment, and neuroinflammation. Conclusions We concluded that sevoflurane exposure can induce an increased level of neuroinflammation, microglial activation, cognitive dysfunction, and anxiety-like behaviors in rats. HCN2 channel, as the target of sevoflurane action, mediates this process. HCN2 might be a target for the treatment and prevention of sevoflurane-induced PND.

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“…Pyramidal neurons in the cortical lamina IV were identified due to optically evoked EPSP to optogenetic stimulation of thalamocortical relay neurons and by visual control (Feldmeyer, 2012 ). Thalamocortical relay neurons of the thalamic ventrobasal complex were identified visually and by means of their unique electrophysiologic properties (Schwerin et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

s-ketamine enhances thalamocortical and corticocortical synaptic transmission in acute murine brain slices via increased AMPA-receptor-mediated pathways

Bieber

Schwerin

Kreuzer

et al. 2022

Front. Syst. Neurosci.

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Despite ongoing research efforts and routine clinical use, the neuronal mechanisms underlying the anesthesia-induced loss of consciousness are still under debate. Unlike most anesthetics, ketamine increases thalamic and cortical activity. Ketamine is considered to act via a NMDA-receptor antagonism-mediated reduction of inhibition, i.e., disinhibition. Intact interactions between the thalamus and cortex constitute a prerequisite for the maintenance of consciousness and are thus a promising target for anesthetics to induce loss of consciousness. In this study, we aim to characterize the influence of s-ketamine on the thalamocortical network using acute brain-slice preparation. We performed whole-cell patch-clamp recordings from pyramidal neurons in cortical lamina IV and thalamocortical relay neurons in acute brain slices from CB57BL/6N mice. Excitatory postsynaptic potentials (EPSPs) were obtained via electrical stimulation of the cortex with a bipolar electrode that was positioned to lamina II/III (electrically induced EPSPs, eEPSPs) or via optogenetic activation of thalamocortical relay neurons (optogenetically induced EPSPs, oEPSPs). Intrinsic neuronal properties (like resting membrane potential, membrane threshold for action potential generation, input resistance, and tonic action potential frequency), as well as NMDA-receptor-dependent and independent spontaneous GABAA-receptor-mediated inhibitory postsynaptic currents (sIPSCs) were evaluated. Wilcoxon signed-rank test (level of significance < 0.05) served as a statistical test and Cohen’s U3_1 was used to determine the actual effect size. Within 20 min, s-ketamine (5 μM) significantly increased both intracortical eEPSPs as well as thalamocortical oEPSPs. NMDA-receptor-mediated intracortical eEPSPs were significantly reduced. Intrinsic neuronal properties of cortical pyramidal neurons from lamina IV and thalamocortical relay neurons in the ventrobasal thalamic complex were not substantially affected. Neither a significant effect on NMDA-receptor-dependent GABAA sIPSCs (thought to underly a disinhibitory effect) nor a reduction of NMDA-receptor independent GABAA sIPSCs was observed. Both thalamocortical and intracortical AMPA-receptor-mediated EPSPs were significantly increased.In conclusion, our findings show no evidence for a NMDA-receptor antagonism-based disinhibition, but rather suggest an enhanced thalamocortical and intracortical synaptic transmission, which appears to be driven via increased AMPA-receptor-mediated transmission.

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Attenuation of Native Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Volatile Anesthetic Sevoflurane in Mouse Thalamocortical Relay Neurons

Cited by 6 publications

References 76 publications

Volatile anesthetics inhibit presynaptic cGMP signaling to depress presynaptic excitability in rat hippocampal neurons

Volatile anesthetics inhibit presynaptic cGMP signaling to depress presynaptic excitability in rat hippocampal neurons

PEX5R/Trip8b-HCN2 channel regulating neuroinflammation involved in perioperative neurocognitive disorders

s-ketamine enhances thalamocortical and corticocortical synaptic transmission in acute murine brain slices via increased AMPA-receptor-mediated pathways

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