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

Xianshu Ju,Jianchen Cui,Seok-Hwa Yoon,Gi Ryang Kweon,Yulim Lee,Yong Sup Shin,Woosuk Chung,Sungho Yoo,Boohwi Hong,Won Hyung Lee,Youngkwon Ko,Yoon Hee Kim,Jun Young Heo,Sangil Park,Min Jeong Ryu

doi:10.3389/fncel.2020.00004

Abstract

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.

Highlights

Preclinical animal studies continuously report possible neurotoxic effects from anesthesia in young rodents, sheep, and non-human primates (Olutoye et al, 2016; Jevtovic-Todorovic, 2018)
To gain further insight and to identify a possible molecular target for preventing such anesthesia-induced changes, we focused on the mammalian target of rapamycin (mTOR) pathway due to the fact that mTOR signaling regulates mitochondrial function (Ramanathan and Schreiber, 2009; Morita et al, 2015, 2017), dendritic spine formation, AMPA receptor synthesis, and excitatory synaptic transmission (Bockaert and Marin, 2015)
Our results indicate that the mTOR pathway is associated with the changes that occur after anesthetic exposure in late postnatal male mice

Summary

Introduction

Preclinical animal studies continuously report possible neurotoxic effects from anesthesia in young rodents, sheep, and non-human primates (Olutoye et al, 2016; Jevtovic-Todorovic, 2018). Previous studies show that anesthesia-induced neurotoxicity depends on their neurodevelopmental stage. While anesthesia induces neuronal cell death in neonatal mice, the same anesthetics induces excitatory/inhibitory imbalance in late postnatal mice (Briner et al, 2010; Chung et al, 2017a; Ju et al, 2019). Excitatory/inhibitory imbalance has been linked to diverse neurodevelopmental disorders (Meredith, 2015; Lee et al, 2017). Because most procedures requiring anesthesia in humans are performed during the postnatal period, these anesthesia-induced changes in late postnatal mice may be of great importance, as the neurodevelopment of mice during this stage may be equivalent to the neurodevelopment of human infants (Workman et al, 2013). The mechanisms underlying anesthesia-induced changes in late postnatal mice are still not completely understood

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Conclusion