Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice.

Sunan Gao,Weiwei Yan,Jian Lu,Siyu Zhang,Daqing Pei,Yunjian Ni,Xiaoyan Tao,Hongmei Zhou,Shuai Kang

doi:10.3389/fnagi.2021.628541

Abstract

Postoperative cognitive dysfunction increases mortality and morbidity in perioperative patients and has become a major concern for patients and caregivers. Previous studies demonstrated that synaptic plasticity is closely related to cognitive function, anesthesia and surgery inhibit synaptic function. In central nervous system, autophagy is vital to synaptic plasticity, homeostasis of synapticproteins, synapse elimination, spine pruning, proper axon guidance, and when dysregulated, is associated with behavioral and memory functions disorders. The mammalian target of rapamycin (mTOR) negatively regulates the process of autophagy. This study aimed to explore whether rapamycin can ameliorate anesthesia/surgery-induced cognitive deficits by inhibiting mTOR, activating autophagy and rising synaptic plasticity-related proteins in the hippocampus. Aged C57BL/6J mice were used to establish POCD models with exploratory laparotomy under isoflurane anesthesia. The Morris Water Maze (MWM) was used to measure reference memory after anesthesia and surgery. The levels of mTOR phosphorylation (p-mTOR), Beclin-1 and LC3-II were examined on postoperative days 1, 3 and 7 by western blotting. The levels of synaptophysin (SYN) and postsynaptic density protein 95 (PSD-95) in the hippocampus were also examined by western blotting. Here we showed that anesthesia/surgery impaired reference memory and induced the activation of mTOR, decreased the expression of autophagy-related proteins such as Beclin-1 and LC3-II. A corresponding decline in the expression of neuronal/synaptic, plasticity-related proteins such as SYN and PSD-95 was also observed. Pretreating mice with rapamycin inhibited the activation of mTOR and restored autophagy function, also increased the expression of SYN and PSD-95. Furthermore, anesthesia/surgery-induced learning and memory deficits were also reversed by rapamycin pretreatment. In conclusion, anesthesia/surgery induced mTOR hyperactivation and autophagy impairments, and then reduced the levels of SYN and PSD-95 in the hippocampus. An mTOR inhibitor, rapamycin, ameliorated anesthesia/surgery-related cognitive impairments by inhibiting the mTOR activity, inducing activation of autophagy, enhancing SYN and PSD-95 expression.

Highlights

Postoperative cognitive dysfunction (POCD) is a complication of the central nervous system after anesthesia and surgery, mainly manifested in the deterioration of cognitive function, especially learning and memory, attention (Abildstrom et al, 2000; Berger et al, 2015; Steinmetz and Rasmussen, 2016; Holmgaard et al, 2019)
In order to investigate whether the hyperactivation of p-Mammalian target of rapamycin (mTOR) was involved in the reduction of light chain 3 (LC3)-II and Beclin-1 levels, the present study examined the effect of rapamycin on the levels of LC3-II and Beclin-1 in the homogenates of the hippocampal tissue using western blot analysis (Figure 4A)
Inhibiting the mTOR hyperactivation with rapamycin administration improved anesthesia/surgery-induced memory and cognitive dysfunction by activating autophagy and increasing synaptic plasticity related proteins SYN and PSD-95 expression. This present study suggests that inhibiting excessive activity of mTOR and activating autophagy may provide a restorative method for the treatment of anesthesia/surgery-induced cognitive impairment

Summary

Introduction

Postoperative cognitive dysfunction (POCD) is a complication of the central nervous system after anesthesia and surgery, mainly manifested in the deterioration of cognitive function, especially learning and memory, attention (Abildstrom et al, 2000; Berger et al, 2015; Steinmetz and Rasmussen, 2016; Holmgaard et al, 2019). Inhibition of mTOR, by rapamycin, reestablishes the LC3-II levels and restores the levels of synaptic plasticity-related proteins including PSD-95, SHANK3 and p62. These suggest that mTOR-regulated autophagy system plays an important role in the synaptic plasticity-related proteins alterations. In the present study, we explored that whether the modulation of the autophagy activation, by inhibiting mTOR with rapamycin administration, was capable of restoring alterations in the decline of synaptic plasticity-related proteins and the cognitive impairment induced by anesthesia/surgery

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