Background: The thalamus is thought to be crucially involved in the anesthetic state. Here, we investigated the effect of the inhaled anesthetic xenon on stimulus-evoked thalamocortical network activity and on excitability of thalamocortical neurons. Because hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are key regulators of neuronal excitability in the thalamus, the effect of xenon on HCN channels was examined. Methods: The effects of xenon on thalamocortical network activity were investigated in acutely prepared brain slices from adult wild-type and HCN2 knockout mice by means of voltage-sensitive dye imaging. The influence of xenon on single-cell excitability in brain slices was investigated using the whole-cell patch-clamp technique. Effects of xenon on HCN channels were verified in human embryonic kidney cells expressing HCN2 channels. Results: Xenon concentration-dependently diminished thalamocortical signal propagation. In neurons, xenon reduced HCN channel-mediated I h current amplitude by 33.4 ± 12.2% (at −133 mV; n = 7; P = 0.041) and caused a left-shift in the voltage of half-maximum activation ( V 1/2 ) from −98.8 ± 1.6 to −108.0 ± 4.2 mV (n = 8; P = 0.035). Similar effects were seen in human embryonic kidney cells. The impairment of HCN channel function was negligible when intracellular cyclic adenosine monophosphate level was increased. Using HCN2 −/− mice, we could demonstrate that xenon did neither attenuate in vitro thalamocortical signal propagation nor did it show sedating effects in vivo . Conclusions: Here, we clearly showed that xenon impairs HCN2 channel function, and this impairment is dependent on intracellular cyclic adenosine monophosphate levels. We provide evidence that this effect reduces thalamocortical signal propagation and probably contributes to the hypnotic properties of xenon. Abstract In thalamocortical slices, xenon evoked hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channel-dependent impairment of neuronal excitability and reduced thalamocortical signal propagation. In HCN2 knockout mice, the sedative effect of xenon was not observed. The data suggest that depression of thalamocortical signal propagation that is in part mediated by HCN2 channels might contribute to the anesthetic action of xenon.

Background: Tranexamic acid (TXA) is commonly used to reduce blood loss in cardiac surgery and in trauma patients. High-dose application of TXA is associated with an increased risk of postoperative seizures. The neuronal mechanisms underlying this proconvulsant action of TXA are not fully understood. In this study, the authors investigated the effects of TXA on neuronal excitability and synaptic transmission in the basolateral amygdala. Methods: Patch clamp recordings and voltage-sensitive dye imaging were performed in acute murine brain slices. Currents through N -methyl- d -aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor type A (GABA A ) receptors were recorded. GABA A receptor–mediated currents were evoked upon electrical stimulation or upon photolysis of caged GABA. TXA was applied at different concentrations. Results: Voltage-sensitive dye imaging demonstrates that TXA (1 mM) reversibly enhances propagation of neuronal excitation (mean ± SEM, 129 ± 6% of control; n = 5). TXA at concentrations of 0.1, 0.3, 1, 5, or 10 mM led to a dose-dependent reduction of GABA A receptor–mediated currents in patch clamp recordings. There was no difference in the half-maximal inhibitory concentration for electrically (0.76 mM) and photolytically (0.84 mM) evoked currents (n = 5 to 9 for each concentration), and TXA did not affect the paired-pulse ratio of GABA A receptor–mediated currents. TXA did not impact glutamatergic synaptic transmission. Conclusions: This study clearly demonstrates that TXA enhances neuronal excitation by antagonizing inhibitory GABAergic neurotransmission. The results provide evidence that this effect is mediated via postsynaptic mechanisms. Because GABA A receptor antagonists are known to promote epileptiform activity, this effect might explain the proconvulsant action of TXA.

Background The memory-blocking properties of general anesthetics are of high clinical relevance and scientific interest. The inhalational anesthetic xenon antagonizes N-methyl-D-aspartate (NMDA) receptors. It is unknown if xenon affects long-term potentiation (LTP), a cellular correlate for memory formation. In hippocampal brain slices, the authors investigated in area CA1 whether xenon affects LTP, NMDA receptor-mediated neurotransmission, and intracellular calcium concentrations. Methods In sagittal murine hippocampal brain slices, the authors investigated the effects of xenon on LTP by recording excitatory postsynaptic field potentials. Using fluorometric calcium imaging, the authors tested the influence of xenon on calcium influx during high-frequency stimulation. In addition, using the patch-clamp technique, the xenon effect on synaptic and extrasynaptic NMDA receptors and L-type calcium channels was examined. Results In the absence of xenon, high-frequency stimulation reliably induced LTP and potentiated field potential slopes to (mean ± SEM) 127.2 ± 5.8% (P < 0.001). In the presence of xenon, high-frequency stimulation induced only a short-term potentiation, and field potentials returned to baseline level after 15-20 min (105.9 ± 2.9%; P = 0.090). NMDA receptor-mediated excitatory postsynaptic currents were reduced reversibly by xenon to 65.9 ± 9.4% (P = 0.007) of control. When extrasynaptic receptors were activated, xenon decreased NMDA currents to 58.2 ± 5.8% (P < 0.001). Xenon reduced the increase in intracellular calcium during high-frequency stimulation without affecting L-type calcium channels. Conclusions N-methyl-D-aspartate receptor activation is crucial for the induction of CA1 LTP. Thus, the depression of NMDA receptor-mediated neurotransmission presumably contributes to the blockade of LTP under xenon. Because LTP is assumed to be involved in learning and memory, its blockade might be a key mechanism for xenon's amnestic properties.

Background The molecular mechanisms of the inhalational anesthetic xenon are not yet fully understood. Recently, the authors showed that xenon reduces both N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic transmission in a brain slice preparation of the amygdala. In the current study, the authors examined the effects of xenon on synaptic transmission in the prefrontal cortex and the spinal cord dorsal horn (substantia gelatinosa). Methods In rodent brain or spinal cord slice preparations, the authors used patch clamp technique to investigate the impact of xenon on NMDA and AMPA receptor-mediated excitatory postsynaptic currents, as well as on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents. The currents were either evoked upon electrical stimulation (NMDA-eEPSCs and AMPA-eEPSCs) or upon photolysis of caged L-glutamate (p-NMDA-Cs and p-AMPA-Cs). In addition, the authors investigated the effects of xenon on AMPA receptor-mediated miniature excitatory postsynaptic currents. Results In both central nervous system regions, xenon had virtually no effect on inhibitory postsynaptic currents. In the prefrontal cortex (spinal cord), xenon reversibly reduced NMDA-eEPSCs to approximately 58% (72%) and AMPA-eEPSCs to approximately 67% (65%) of control. There was no difference in the xenon-induced reduction of NMDA-eEPSCs and p-NMDA-Cs, or AMPA-eEPSCs and p-AMPA-Cs. Xenon did not affect the frequency of miniature excitatory postsynaptic currents but reduced their amplitude. Conclusions In the current study, the authors found that xenon depresses NMDA and AMPA receptor-mediated synaptic transmission in the prefrontal cortex and the substantia gelatinosa without affecting gamma-aminobutyric acid type A receptor-mediated synaptic transmission. These results provide evidence that the effects of xenon are primarily due to postsynaptic mechanisms.

Background The neuronal and molecular targets of the inhalational general anesthetic xenon are a matter of debate. The current knowledge is largely based on studies using neurons in culture or heterologous expression systems. In the current study, the authors evaluated for the first time the effect of xenon on synaptic transmission in the basolateral amygdala in an in vitro brain slice preparation of the mouse. Methods A patch clamp technique was used to evaluate the effects of xenon on N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs), as well as on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents. The currents were either evoked upon electrical stimulation (NMDA-eEPSCs, AMPA-eEPSCs) or upon focal, laser-guided photolysis of caged l-glutamate (p-NMDA-Cs, p-AMPA-Cs). In addition, the authors investigated the effects of xenon on miniature EPSCs. Results Xenon reversibly reduced basal synaptic transmission but had no effect on gamma-aminobutyric acid type A receptor-mediated inhibitory synaptic transmission. Xenon concentration-dependently diminished NMDA-eEPSCs and p-NMDA-Cs to the same amount. Likewise, xenon-induced reduction of AMPA-eEPSCs and p-AMPA-Cs did not differ. Xenon did not affect the frequency of miniature EPSCs but reduced their amplitude. Conclusions In the current study, xenon considerably depressed NMDA and AMPA receptor-mediated synaptic transmission in the basolateral amygdala without affecting inhibitory synaptic transmission. The results provide evidence that the effects of xenon on NMDA- and AMPA-EPSCs are primarily mediated via postsynaptic mechanisms.

Background The volatile anesthetic isoflurane depresses glutamatergic transmission. In this study, the authors investigated the effects of isoflurane on the induction of long-term potentiation (LTP) and long-term depression (LTD) in slices from the juvenile and adult mouse hippocampus. Both forms of synaptic plasticity involve the activation of glutamate receptors. Methods Field excitatory postsynaptic potentials and excitatory postsynaptic currents from neurons in the CA1 area were evoked by stimulation of the Schaffer collateral-commissural pathway. Two independent synaptic inputs were stimulated. Clinically relevant concentrations (0.2-0.3 mM) of isoflurane were added to the perfusion solution. Results Field excitatory postsynaptic potentials from slices of juvenile and adult mice were depressed to 37.3 +/- 6.1% and 58.3 +/- 7.4%, respectively, and excitatory postsynaptic currents were reduced to 36.7 +/- 5.4% by isoflurane. A brief tetanic stimulation (100 Hz, 1 s) induced stable LTP of field excitatory postsynaptic potentials. In the presence of isoflurane, tetanization failed to induce LTP. The effect of isoflurane on LTP induction was reversible and could be prevented by antagonizing gamma-aminobutyric acid type A receptors (GABAA). Low-frequency stimulation (1 Hz/900 pulses) induced LTD. In the presence of isoflurane, low-frequency stimulation failed to induce LTD. Conclusions The prevention of the isoflurane-induced depression of LTP by the GABAA antagonist picrotoxin suggests an involvement of GABAA receptors. An enhancement of the efficacy of GABA-mediated inhibitory synaptic transmission prevents the depolarization of the postsynaptic membrane during tetanus, necessary for the induction of use-dependent alteration of synaptic strength. An impairment of these processes may be a cause for the transient loss of recall and cognitive impairment after anesthesia in juvenile and adult brains.