As thalamocortical relay neurons are ascribed a crucial role in signal propagation and information processing, they have attracted considerable attention as potential targets for anesthetic modulation. In this study, we analyzed the effects of different concentrations of sevoflurane on the excitability of thalamocortical relay neurons and hyperpolarization-activated, cyclic-nucleotide gated (HCN) channels, which play a decisive role in regulating membrane properties and rhythmic oscillatory activity. The effects of sevoflurane on single-cell excitability and native HCN channels were investigated in acutely prepared brain slices from adult wild-type mice with the whole-cell patch-clamp technique, using voltage-clamp and current-clamp protocols. Sevoflurane dose-dependently depressed membrane biophysics and HCN-mediated parameters of neuronal excitability. Respective half-maximal inhibitory and effective concentrations ranged between 0.30 (95% CI, 0.18–0.50) mM and 0.88 (95% CI, 0.40–2.20) mM. We witnessed a pronounced reduction of HCN dependent I_h current amplitude starting at a concentration of 0.45 mM [relative change at −133 mV; 0.45 mM sevoflurane: 0.85 (interquartile range, 0.79–0.92), n = 12, p = 0.011; 1.47 mM sevoflurane: 0.37 (interquartile range, 0.34–0.62), n = 5, p < 0.001] with a half-maximal inhibitory concentration of 0.88 (95% CI, 0.40–2.20) mM. In contrast, effects on voltage-dependent channel gating were modest with significant changes only occurring at 1.47 mM [absolute change of half-maximal activation potential; 1.47 mM: −7.2 (interquartile range, −10.3 to −5.8) mV, n = 5, p = 0.020]. In this study, we demonstrate that sevoflurane inhibits the excitability of thalamocortical relay neurons in a concentration-dependent manner within a clinically relevant range. Especially concerning its effects on native HCN channel function, our findings indicate substance-specific differences in comparison to other anesthetic agents. Considering the importance of HCN channels, the observed effects might mechanistically contribute to the hypnotic properties of sevoflurane.

丘脑皮质中枢神经元在信号传播和信息处理中起着至关重要的作用，因此它们作为麻醉剂调制的潜在靶点已引起了广泛的关注。在这项研究中，我们分析了不同浓度的七氟醚对丘脑皮质中继神经元和超极化激活的环核苷酸门控（HCN）通道的兴奋性的影响，它们在调节膜的性质和节律性振荡活动中起决定性作用。使用电压钳位和电流钳位方案，采用全细胞膜片钳技术在成年野生型小鼠的急性制备脑切片中研究了七氟醚对单细胞兴奋性和天然HCN通道的影响。七氟醚剂量依赖性抑制膜生物物理学和神经元兴奋性的HCN介导参数。半数抑制和有效浓度分别在0.30（95％CI，0.18–0.50）mM和0.88（95％CI，0.40–2.20）mM之间。我们目睹了HCN依赖I的明显减少_h电流振幅始于0.45 mM的浓度[在-133 mV时的相对变化；0.45 mM七氟醚：0.85（四分位间距，0.79-0.92），ñ = 12 p= 0.011; 1.47 mM七氟醚：0.37（四分位数范围，0.34–0.62），ñ = 5 p<0.001]，最大半数抑制浓度为0.88（95％CI，0.40–2.20）mM。相反，对电压依赖性通道门控的影响适中，只有在1.47 mM时才发生显着变化[半最大激活电位的绝对变化；1.47 mM：-7.2（四分位范围，-10.3至-5.8）mV，ñ = 5 p= 0.020]。在这项研究中，我们证明七氟醚在临床相关范围内以浓度依赖性方式抑制丘脑皮质中继神经元的兴奋性。特别是关于其对天然HCN通道功能的影响，我们的发现表明与其他麻醉剂相比，特定物质的差异。考虑到HCN通道的重要性，观察到的效应可能在机械上有助于七氟醚的催眠特性。