Sevoflurane-induced overexpression of extrasynaptic α5-GABAAR via the RhoA/ROCK2 pathway impairs cognitive function in aged mice

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Aging Cell Pub Date : 2024-06-02 DOI:10.1111/acel.14209
Zhun Wang, Jinpeng Dong, Mengxue Zhang, Sixuan Wang, Jiangnan Wu, Shengran Wang, Yuan Luo, Yongan Wang, Yiqing Yin
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Abstract

Perioperative neurocognitive disorder (PND) is a serious neurologic complication in aged patients and might be associated with sevoflurane exposure. However, the specific pathogenesis is still unclear. The distribution of α5-GABAAR, a γ-aminobutyric acid type A receptor (GABAAR) subtype, at extrasynaptic sites is influenced by the anchor protein radixin, whose phosphorylation is regulated via the RhoA/ROCK2 signaling pathway and plays a crucial role in cognition. However, whether sevoflurane affects the ability of radixin phosphorylation to alter extrasynaptic receptor expression is unknown. Aged mice were exposed to sevoflurane to induce cognitive impairment. Both total proteins and membrane proteins were extracted for analysis. Cognitive function was evaluated using the Morris water maze and fear conditioning test. Western blotting was used to determine the expression of ROCK2 and the phosphorylation of radixin. Furthermore, the colocalization of p-radixin and α5-GABAAR was observed. To inhibit ROCK2 activity, either an adeno-associated virus (AAV) or fasudil hydrochloride was administered. Aged mice treated with sevoflurane exhibited significant cognitive impairment accompanied by increased membrane expression of α5-GABAAR. Moreover, the colocalization of α5-GABAAR and p-radixin increased after treatment with sevoflurane, and this change was accompanied by an increase in ROCK2 expression and radixin phosphorylation. Notably, inhibiting the RhoA/ROCK2 pathway significantly decreased the distribution of extrasynaptic α5-GABAAR and improved cognitive function. Sevoflurane activates the RhoA/ROCK2 pathway and increases the phosphorylation of radixin. Excess α5-GABAAR is anchored to extrasynaptic sites and impairs cognitive ability in aged mice. Fasudil hydrochloride administration improves cognitive function.

Abstract Image

Abstract Image

七氟醚通过RhoA/ROCK2途径诱导突触外α5-GABAAR的过表达会损害老年小鼠的认知功能
围手术期神经认知障碍(PND)是老年患者的一种严重神经并发症,可能与七氟烷暴露有关。然而,具体的发病机制仍不清楚。α5-GABAAR是一种γ-氨基丁酸A型受体(GABAAR)亚型,其在突触外位点的分布受锚蛋白radixin的影响,radixin的磷酸化通过RhoA/ROCK2信号通路调节,在认知中起着至关重要的作用。然而,七氟烷是否会影响radixin磷酸化改变突触外受体表达的能力尚不清楚。将老年小鼠暴露于七氟烷以诱导认知障碍。提取总蛋白和膜蛋白进行分析。使用莫里斯水迷宫和恐惧条件反射测试评估认知功能。用 Western 印迹法测定 ROCK2 的表达和 radixin 的磷酸化。此外,还观察到了p-radixin和α5-GABAAR的共定位。为了抑制 ROCK2 的活性,给小鼠注射了腺相关病毒(AAV)或盐酸法舒地尔。接受七氟醚治疗的老年小鼠表现出明显的认知障碍,同时α5-GABAAR的膜表达增加。此外,经七氟醚处理后,α5-GABAAR 和 p-radixin 的共定位增加,这一变化伴随着 ROCK2 表达和 radixin 磷酸化的增加。值得注意的是,抑制 RhoA/ROCK2 通路可显著减少突触外 α5-GABAAR 的分布并改善认知功能。七氟烷可激活 RhoA/ROCK2 通路并增加 radixin 的磷酸化。过多的α5-GABAAR锚定在突触外位点,损害了老年小鼠的认知能力。盐酸法舒地尔能改善认知功能。
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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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
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