A new mechanism of consciousness recovery from anesthesia regulated by K+-Cl– cotransporter KCC2

Brain-X Pub Date : 2023-06-01 DOI:10.1002/brx2.19
Jinwei Zhang
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However, prior to the recent work of Hu et al.,<span><sup>2</sup></span> research had not yet examined the core of consciousness recovery.</p><p>Hu et al. presented findings indicating that consciousness recovery is an active, not passive, process.<span><sup>3</sup></span> So-called passive recovery is merely an easily observable, intuitive, and superficial phenomenon and is not the essence of consciousness recovery. The authors used a combination of the traditional righting reflex test and a newly established scale to assess the level of consciousness in animals during the loss of consciousness following anesthetic administration. In mice, the administration of propofol, pentobarbital, or ketamine via intraperitoneal injection resulted in loss of the righting reflex (LORR) within 1 min and a righting reflex score of less than 3 within 15–20 min. The authors defined the state of mice with a consciousness score of less than 3 as the minimal response state (MRS) (Figure 1A). They then found that the active process of consciousness recovery is driven by inherent dynamics within the brain, initiated by a neurochemical reaction triggered by the ubiquitin degradation of the K<sup>+</sup>-Cl<sup>−</sup> cotransporter-2 (KCC2), mediated by ubiquitin ligase Fbxl4 (F-box and leucine-rich repeat protein 4), in the ventral posteromedial nucleus (VPM) of the thalamus. Interestingly, the total amount of KCC2 (tKCC2) was observed to decrease from the awake state to MRS and increase from MRS to the recovery of the righting reflex (RRR), and with opposite changes in the amount of KCC2 Thr1007 phosphorylation (pKCC2) in the thalamus and hypothalamus (Figure 1B). The decreased tKCC2 and increased pKCC2 during MRS resulted in lower KCC2 activity, leading to elevated intraneuronal Cl<sup>−</sup> levels [Cl<sup>−</sup>]<sub>\n <i>i</i>\n </sub>. This facilitated γ-aminobutyric acid (GABA)-driven Cl<sup>−</sup> output, which in turn led to GABA<sub>A</sub> receptor-mediated depolarization in VPM neurons (Figure 1C). Further in vitro experiments have shown that the interaction between KCC2 and Fbxl4 depends on the phosphorylation of KCC2 at Thr1007, which plays a critical role in the ubiquitination of KCC2 during propofol anesthesia. As a result, VPM neurons are disinhibited through GABA<sub>A</sub> receptor-mediated signaling, which accelerates the recovery of excitability and consciousness arousal.</p><p>Hu et al. discovered that ubiquitin degradation of KCC2 and its phosphorylation at the Thr1007 site in the VPM brain region is a crucial mechanism for active consciousness recovery.<span><sup>2</sup></span> Inhibiting the phosphorylation of the KCC2 Thr1007 site specifically in the VPM brain region of mice under general anesthesia increased the level of KCC2 protein, further prolonging the loss of consciousness and exacerbating the anesthetic effect. KCC2 antagonists can block this effect, indicating a promising therapeutic approach. This mechanism is independent of the pharmacological properties and molecular targets of general anesthetics, including well-known targets like <i>N</i>-methyl-D-aspartate (NMDA) and GABA<sub>A</sub> receptors. KCC2 ubiquitin degradation-induced disinhibition of VPM neurons can trigger the formation of highly sensitive local neural networks that have high-quality communication links between them, leading to the reconstruction of neural circuits.</p><p>Hu et al.'s findings present a novel perspective on potential approaches for restoring consciousness in complex medical cases. They studied four anesthetics, including propofol, and discovered a shared mechanism for consciousness restoration. Remarkably, ketamine, which targets a distinct pathway from propofol, also functions via this mechanism. Their research additionally indicates that the degradation of KCC2 by ubiquitin and subsequent events may cause anesthetic epilepsy. However, further investigation is necessary to determine the applicability of these findings to humans. Examining the involvement of the WNK-SPAK/OSR1 signaling pathway in the active recovery of consciousness from propofol anesthesia could be worthwhile since it is the primary upstream pathway for KCC2 Thr1007 phosphorylation.<span><sup>3</sup></span> Overall, exploring the neural and molecular substrates involved in reconnecting neural networks may provide insights into the nature of consciousness.</p><p>\n <b>Jinwei Zhang</b>: Writing—original draft; Writing—review &amp; editing.</p><p>The author declares no conflicts of interest.</p>","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.19","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain-X","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/brx2.19","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 1

Abstract

Neuroscience faces a puzzle in understanding the mechanism of general anesthesia. In the past, it was widely believed that recovery from anesthesia was a passive process caused by the breakdown of anesthetic agents. However, recent studies have challenged this view. For instance, activating specific neural circuits can promote the recovery of consciousness,1 indicating that these circuits is related to consciousness recovery and could play a crucial role in promoting it. However, prior to the recent work of Hu et al.,2 research had not yet examined the core of consciousness recovery.

Hu et al. presented findings indicating that consciousness recovery is an active, not passive, process.3 So-called passive recovery is merely an easily observable, intuitive, and superficial phenomenon and is not the essence of consciousness recovery. The authors used a combination of the traditional righting reflex test and a newly established scale to assess the level of consciousness in animals during the loss of consciousness following anesthetic administration. In mice, the administration of propofol, pentobarbital, or ketamine via intraperitoneal injection resulted in loss of the righting reflex (LORR) within 1 min and a righting reflex score of less than 3 within 15–20 min. The authors defined the state of mice with a consciousness score of less than 3 as the minimal response state (MRS) (Figure 1A). They then found that the active process of consciousness recovery is driven by inherent dynamics within the brain, initiated by a neurochemical reaction triggered by the ubiquitin degradation of the K+-Cl cotransporter-2 (KCC2), mediated by ubiquitin ligase Fbxl4 (F-box and leucine-rich repeat protein 4), in the ventral posteromedial nucleus (VPM) of the thalamus. Interestingly, the total amount of KCC2 (tKCC2) was observed to decrease from the awake state to MRS and increase from MRS to the recovery of the righting reflex (RRR), and with opposite changes in the amount of KCC2 Thr1007 phosphorylation (pKCC2) in the thalamus and hypothalamus (Figure 1B). The decreased tKCC2 and increased pKCC2 during MRS resulted in lower KCC2 activity, leading to elevated intraneuronal Cl levels [Cl] i . This facilitated γ-aminobutyric acid (GABA)-driven Cl output, which in turn led to GABAA receptor-mediated depolarization in VPM neurons (Figure 1C). Further in vitro experiments have shown that the interaction between KCC2 and Fbxl4 depends on the phosphorylation of KCC2 at Thr1007, which plays a critical role in the ubiquitination of KCC2 during propofol anesthesia. As a result, VPM neurons are disinhibited through GABAA receptor-mediated signaling, which accelerates the recovery of excitability and consciousness arousal.

Hu et al. discovered that ubiquitin degradation of KCC2 and its phosphorylation at the Thr1007 site in the VPM brain region is a crucial mechanism for active consciousness recovery.2 Inhibiting the phosphorylation of the KCC2 Thr1007 site specifically in the VPM brain region of mice under general anesthesia increased the level of KCC2 protein, further prolonging the loss of consciousness and exacerbating the anesthetic effect. KCC2 antagonists can block this effect, indicating a promising therapeutic approach. This mechanism is independent of the pharmacological properties and molecular targets of general anesthetics, including well-known targets like N-methyl-D-aspartate (NMDA) and GABAA receptors. KCC2 ubiquitin degradation-induced disinhibition of VPM neurons can trigger the formation of highly sensitive local neural networks that have high-quality communication links between them, leading to the reconstruction of neural circuits.

Hu et al.'s findings present a novel perspective on potential approaches for restoring consciousness in complex medical cases. They studied four anesthetics, including propofol, and discovered a shared mechanism for consciousness restoration. Remarkably, ketamine, which targets a distinct pathway from propofol, also functions via this mechanism. Their research additionally indicates that the degradation of KCC2 by ubiquitin and subsequent events may cause anesthetic epilepsy. However, further investigation is necessary to determine the applicability of these findings to humans. Examining the involvement of the WNK-SPAK/OSR1 signaling pathway in the active recovery of consciousness from propofol anesthesia could be worthwhile since it is the primary upstream pathway for KCC2 Thr1007 phosphorylation.3 Overall, exploring the neural and molecular substrates involved in reconnecting neural networks may provide insights into the nature of consciousness.

Jinwei Zhang: Writing—original draft; Writing—review & editing.

The author declares no conflicts of interest.

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K+-Cl协同转运蛋白KCC2调节麻醉后意识恢复的新机制
神经科学在理解全身麻醉的机制方面面临着一个难题。过去,人们普遍认为,从麻醉中恢复是一个由麻醉剂分解引起的被动过程。然而,最近的研究对这一观点提出了质疑。例如,激活特定的神经回路可以促进意识的恢复,1表明这些回路与意识恢复有关,并可能在促进意识恢复中发挥关键作用。然而,在Hu等人最近的工作之前。,2项研究尚未检验意识恢复的核心。胡等。研究结果表明,意识恢复是一个主动而非被动的过程。3所谓的被动恢复只是一种容易观察、直观和肤浅的现象,并不是意识恢复的本质。作者使用传统的翻正反射测试和新建立的量表相结合的方法来评估动物在麻醉后意识丧失期间的意识水平。在小鼠中,通过腹膜内注射丙泊酚、戊巴比妥或氯胺酮导致1分钟内翻正反射(LORR)丧失,15-20分钟内翻右反射得分低于3。作者将意识评分低于3的小鼠的状态定义为最小反应状态(MRS)(图1A)。然后,他们发现意识恢复的主动过程是由大脑内固有的动力学驱动的,由丘脑腹后内侧核(VPM)中的泛素连接酶Fbxl4(F-box和富含亮氨酸的重复蛋白4)介导的K+-Cl−协同转运蛋白2(KCC2)的泛素降解引发的神经化学反应引发。有趣的是,观察到KCC2的总量(tKCC2)从清醒状态减少到MRS,从MRS增加到翻正反射(RRR)的恢复,丘脑和下丘脑中KCC2 Thr1007磷酸化(pKCC2)的量发生相反的变化(图1B)。MRS期间tKCC2的减少和pKCC2的增加导致KCC2活性降低,导致神经内Cl−水平[Cl−]i升高。这促进了γ-氨基丁酸(GABA)驱动的Cl−输出,进而导致VPM神经元中GABAA受体介导的去极化(图1C)。进一步的体外实验表明,KCC2和Fbxl4之间的相互作用取决于KCC2在Thr1007的磷酸化,Thr1007在丙泊酚麻醉期间KCC2的泛素化中起着关键作用。因此,VPM神经元通过GABAA受体介导的信号传导被解除抑制,从而加速兴奋性和意识觉醒的恢复。胡等。发现KCC2的泛素降解及其在VPM脑区Thr1007位点的磷酸化是主动意识恢复的关键机制,进一步延长了意识的丧失并加剧了麻醉效果。KCC2拮抗剂可以阻断这种作用,这表明一种有前景的治疗方法。这种机制独立于全身麻醉剂的药理学特性和分子靶标,包括众所周知的靶标,如N-甲基-D-天冬氨酸(NMDA)和GABAA受体。KCC2泛素降解诱导的VPM神经元的去抑制可以触发高度敏感的局部神经网络的形成,这些网络之间具有高质量的通信链路,从而导致神经回路的重建。胡等研究结果为复杂医疗病例中恢复意识的潜在方法提供了一个新的视角。他们研究了包括丙泊酚在内的四种麻醉剂,发现了一种共同的意识恢复机制。值得注意的是,靶向不同于丙泊酚的途径的氯胺酮也通过这种机制发挥作用。他们的研究还表明,泛素对KCC2的降解和随后的事件可能导致麻醉性癫痫。然而,有必要进行进一步的调查,以确定这些发现对人类的适用性。研究WNK-SPAK/OSR1信号通路在丙泊酚麻醉后意识主动恢复中的作用可能是值得的,因为它是KCC2 Thr1007磷酸化的主要上游通路。3总的来说,探索与重新连接神经网络有关的神经和分子底物可以深入了解意识的本质。张金伟:写作——初稿;写作——复习&;编辑。提交人声明没有利益冲突。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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