Inhibition of unfolded protein response prevents post-anesthesia neuronal hyperactivity and synapse loss in aged mice,Aging Cell

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Inhibition of unfolded protein response prevents post-anesthesia neuronal hyperactivity and synapse loss in aged mice
Aging Cell ( IF 8.0 ) Pub Date : 2022-03-17 , DOI: 10.1111/acel.13592
Kai Chen ₁ , Qiuping Hu ₁ , Riya Gupta ₂ , Jessie Stephens ₃ , Zhongcong Xie ₄ , Guang Yang ₁

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Delirium is the most common postoperative complication in older patients after prolonged anesthesia and surgery and is associated with accelerated cognitive decline and dementia. The neuronal pathogenesis of postoperative delirium is largely unknown. The unfolded protein response (UPR) is an adaptive reaction of cells to perturbations in endoplasmic reticulum function. Dysregulation of UPR has been implicated in a variety of diseases including Alzheimer's disease and related dementias. However, whether UPR plays a role in anesthesia-induced cognitive impairment remains unexplored. By performing in vivo calcium imaging in the mouse frontal cortex, we showed that exposure of aged mice to the inhalational anesthetic sevoflurane for 2 hours resulted in a marked elevation of neuronal activity during recovery, which lasted for at least 24 hours after the end of exposure. Concomitantly, sevoflurane anesthesia caused a prolonged increase in phosphorylation of PERK and eIF2α, the markers of UPR activation. Genetic deletion or pharmacological inhibition of PERK prevented neuronal hyperactivity and memory impairment induced by sevoflurane. Moreover, we showed that PERK suppression also reversed various molecular and synaptic changes induced by sevoflurane anesthesia, including alterations of synaptic NMDA receptors, tau protein phosphorylation, and dendritic spine loss. Together, these findings suggest that sevoflurane anesthesia causes abnormal UPR in the aged brain, which contributes to neuronal hyperactivity, synapse loss and cognitive decline in aged mice.

中文翻译：

抑制未折叠的蛋白质反应可防止老年小鼠麻醉后神经元多动和突触丢失

谵妄是老年患者在长期麻醉和手术后最常见的术后并发症，与认知能力加速下降和痴呆有关。术后谵妄的神经元发病机制在很大程度上尚不清楚。未折叠蛋白反应（UPR）是细胞对内质网功能扰动的适应性反应。UPR 的失调与多种疾病有关，包括阿尔茨海默病和相关痴呆症。然而，UPR 是否在麻醉诱导的认知障碍中发挥作用仍有待探索。通过在小鼠额叶皮层进行体内钙成像，我们表明，老年小鼠暴露于吸入麻醉剂七氟烷 2 小时导致恢复期间神经元活动显着升高，暴露结束后至少持续 24 小时。同时，七氟烷麻醉导致 UPR 激活标志物 PERK 和 eIF2α 磷酸化的磷酸化延长增加。PERK 的基因缺失或药理学抑制可防止七氟烷诱导的神经元多动和记忆障碍。此外，我们发现 PERK 抑制还逆转了七氟烷麻醉诱导的各种分子和突触变化，包括突触 NMDA 受体的改变、tau 蛋白磷酸化和树突状脊柱丢失。总之，这些发现表明，七氟烷麻醉会导致老年大脑的 UPR 异常，从而导致老年小鼠的神经元过度活跃、突触丧失和认知能力下降。

更新日期：2022-03-17

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