Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice
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 functio...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2021.628541/full |
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| author | Sunan Gao Siyu Zhang Hongmei Zhou Xiaoyan Tao Yunjian Ni Daqing Pei Shuai Kang Weiwei Yan Jian Lu |
| author_facet | Sunan Gao Siyu Zhang Hongmei Zhou Xiaoyan Tao Yunjian Ni Daqing Pei Shuai Kang Weiwei Yan Jian Lu |
| author_sort | Sunan Gao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T19:59:44Z |
| format | Article |
| id | doaj.art-53ae6820898e469ba03439a6d49240ac |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-14T19:59:44Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-53ae6820898e469ba03439a6d49240ac2022-12-21T22:49:12ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652021-04-011310.3389/fnagi.2021.628541628541Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged MiceSunan Gao0Siyu Zhang1Hongmei Zhou2Xiaoyan Tao3Yunjian Ni4Daqing Pei5Shuai Kang6Weiwei Yan7Jian Lu8Department of Anesthesiology, Zhejiang Chinese Medical University, Hangzhou City, ChinaDepartment of Anesthesiology, Zhejiang Chinese Medical University, Hangzhou City, ChinaDepartment of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, ChinaDepartment of Nursing, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, ChinaDepartment of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, ChinaDepartment of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, ChinaDepartment of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, ChinaDepartment of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, ChinaDepartment of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, ChinaPostoperative 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.https://www.frontiersin.org/articles/10.3389/fnagi.2021.628541/fullrapamycinmTORpostoperative cognitive dysfunctionagedsynaptic plasticity |
| spellingShingle | Sunan Gao Siyu Zhang Hongmei Zhou Xiaoyan Tao Yunjian Ni Daqing Pei Shuai Kang Weiwei Yan Jian Lu Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice Frontiers in Aging Neuroscience rapamycin mTOR postoperative cognitive dysfunction aged synaptic plasticity |
| title | Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice |
| title_full | Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice |
| title_fullStr | Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice |
| title_full_unstemmed | Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice |
| title_short | Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice |
| title_sort | role of mtor regulated autophagy in synaptic plasticity related proteins downregulation and the reference memory deficits induced by anesthesia surgery in aged mice |
| topic | rapamycin mTOR postoperative cognitive dysfunction aged synaptic plasticity |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2021.628541/full |
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