Data_Sheet_2_The mTOR Inhibitor Rapamycin Prevents General Anesthesia-Induced Changes in Synaptic Transmission and Mitochondrial Respiration in Late Postnatal Mice.PDF

Preclinical animal studies have continuously reported the possibility of long-lasting neurotoxic effects after general anesthesia in young animals. Such studies also show that the neurological changes induced by anesthesia in young animals differ by their neurodevelopmental stage. Exposure to anesthetic agents increase dendritic spines and induce sex-dependent changes of excitatory/inhibitory synaptic transmission in late postnatal mice, a critical synaptogenic period. However, the mechanisms underlying these changes remain unclear. Abnormal activation of the mammalian target of rapamycin (mTOR) signaling pathway, an important regulator of neurodevelopment, has also been shown to induce similar changes during neurodevelopment. Interestingly, previous studies show that exposure to general anesthetics during neurodevelopment can activate the mTOR signaling pathway. This study, therefore, evaluated the role of mTOR signaling after exposing postnatal day (PND) 16/17 mice to sevoflurane, a widely used inhalation agent in pediatric patients. We first confirmed that a 2-h exposure of 2.5% sevoflurane could induce widespread mTOR phosphorylation in both male and female mice. Pretreatment with the mTOR inhibitor rapamycin not only prevented anesthesia-induced mTOR phosphorylation, but also the increase in mitochondrial respiration and male-dependent enhancement of excitatory synaptic transmission. However, the changes in inhibitory synaptic transmission that appear after anesthesia in female mice were not affected by rapamycin pretreatment. Our results suggest that mTOR inhibitors may act as potential therapeutic agents for anesthesia-induced changes in the developing brain.

临床前动物研究表明，在幼年动物中，全身麻醉后可能产生持久的神经毒性效应。此类研究亦表明，麻醉引起的神经学变化在幼年动物中因其神经发育阶段的不同而存在差异。暴露于麻醉剂可增加树突棘并诱导晚期出生小鼠的兴奋性/抑制性突触传递的性别依赖性变化，这是关键的突触发生期。然而，这些变化的潜在机制尚不明确。哺乳动物雷帕霉素靶点（mTOR）信号通路的异常激活，作为神经发育的重要调节因子，亦被证实可在神经发育期间诱导类似的变化。有趣的是，先前的研究显示，神经发育期间暴露于全身麻醉剂可以激活mTOR信号通路。因此，本研究评估了在出生后第16/17天暴露于七氟烷（一种在儿科患者中广泛使用的吸入性麻醉剂）后mTOR信号通路的作用。我们首先证实，2.5%七氟烷的2小时暴露可导致雄性和雌性小鼠中mTOR磷酸化的广泛发生。预先给予mTOR抑制剂雷帕霉素不仅可防止麻醉引起的mTOR磷酸化，还可防止线粒体呼吸的增加以及雄性依赖性的兴奋性突触传递增强。然而，麻醉后雌性小鼠出现的抑制性突触传递的变化并未受到雷帕霉素预先治疗的显著影响。我们的研究结果提示，mTOR抑制剂可能作为潜在的治疗剂，用于治疗麻醉引起的发育中大脑的变化。