Memory impairment induced by exposure to simulated hypobaric hypoxia and phosphoproteomic analysis of hippocampus in mice

Huaping DONG; Zhifeng ZHONG; Peng LI; Pei HUANG; Huaijun TIAN; Jiaxin XIE; Simin ZHOU

doi:10.16016/j.2097-0927.202109090

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Memory impairment induced by exposure to simulated hypobaric hypoxia and phosphoproteomic analysis of hippocampus in mice

Neurosciences | 更新时间：2026-01-09

- Memory impairment induced by exposure to simulated hypobaric hypoxia and phosphoproteomic analysis of hippocampus in mice
- Journal of Army Medical University Vol. 44, Issue 4, Pages: 291-301(2022)
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)高原军事医学系高原作业医学教研室，极端环境医学教育部重点实验室，全军高原医学重点实验室
- 作者简介：
- 基金信息：
  
  the National Natural Science Foundation for Young Scholars of China(81701854);the Youth Training Plan for Medical Science of PLA(20QNPY003)
- DOI：10.16016/j.2097-0927.202109090
  CLC： R322.81;R339.54;R394.3
- Received：22 September 2021，
  
  Revised：2021-10-22，
  
  Published：28 February 2022
- 稿件说明：
移动端阅览
Huaping DONG, Zhifeng ZHONG, Peng LI, et al. Memory impairment induced by exposure to simulated hypobaric hypoxia and phosphoproteomic analysis of hippocampus in mice[J]. Journal of Army Medical University, 2022, 44(4): 291-301.
DOI：

Huaping DONG, Zhifeng ZHONG, Peng LI, et al. Memory impairment induced by exposure to simulated hypobaric hypoxia and phosphoproteomic analysis of hippocampus in mice[J]. Journal of Army Medical University, 2022, 44(4): 291-301. DOI： 10.16016/j.2097-0927.202109090.

摘要

目的

观察低压低氧致小鼠记忆损伤及脑海马体蛋白磷酸化修饰水平的变化，探寻低压低氧引起记忆损伤的关键磷酸化修饰蛋白和通路。

方法

40只7~8周龄雄性C57BL/6小鼠，体质量(20±2)g，按体质量顺序编号后采用随机数字表法分为常氧组和低压低氧组(

=20)。常氧组小鼠在常氧条件下喂养，低压低氧组小鼠在模拟海拔6 000 m的低压舱中喂养7 d。低压低氧暴露结束后进行Morris水迷宫实验和脑海马体组织磷酸化蛋白质组学检测。

结果

Morris水迷宫实验结果显示，与常氧组相比，低压低氧组小鼠逃避潜伏期显著延长[(89.66±3.27)

(38.61±4.83)s，

＜0.01

]

、游泳距离显著增加[(959.2

1±99.61)

(550.39±59.43)cm，

＜0.01

]

。磷酸化蛋白质组学分析共检测到显著差异表达磷酸化肽段136个，其中上调92个，来自79个蛋白；下调44个，来自42个蛋白。GO富集分析结果显示: 这些差异磷酸化修饰蛋白主要分布在突触后密集区、非对称性突触和基底细胞膜，主要参与细胞连接组装、突触构成、突触中囊泡介导的运输、树突发育、认知等生物学过程。KEGG通路富集分析显示: 差异磷酸化修饰蛋白质主要富集在胰岛素分泌、胰液分泌、谷氨酸能突触、内吞和长时程抑制等信号通路。在蛋白质相互作用层面，构成以AGAP2、SYNGAP1、DRP2、DRP3和PSD93等蛋白为核心的蛋白互作网络。

结论

低压低氧可致小鼠记忆损伤脑海马体磷酸化修饰蛋白及通路发生改变，AGAP2、SYNGAP1、DRP2、DRP3和PSD93可能是关键蛋白。

Abstract

Objective

To observe the changes of protein phosphorylation levels in the hippocampus of mice with memory impairment caused by hypobaric hypoxia exposure

and to explore the key phosphorylated proteins and associated pathways involved in memory deficits.

Methods

Forty male C57BL/6 mice (7~8 weeks old

body weight 20±2 g) were randomly and equally divided into normoxic control group (Ctrl) and hypobaric hypoxic group (HH). The Ctrl group was housed under normoxic condition

while the HH group was fed for 7 d in a hypobaric chamber at simulated altitude of 6 000 m. Morris water maze (MWM) test was performed after hypoxia exposure

and the hippocampus tissues of mice were collected for phosphoproteomic analysis.

Results

MWM test showed that the escape latency of mice was significantly longer in the HH group than the Ctrl group (89.66±3.27

38.61±4.83 s

0.01)

and the swimming distance was also remarkably increased in the HH group (959.21±99.61

550.39±59.43 cm

0.01). A total of 136 phosphopeptides with significant difference in expression between the 2 groups were detected by phosphoproteomic analysis

including 92 up-regulated phosphopeptides corresponding to 79 proteins and 44 down-regulated from 42 proteins. Gene Ontology (GO) enrichment analysis revealed that these differentially phosphorylated proteins were primarily distribute

d in postsynaptic density

asymmetric synapse and basal plasma membrane

and were mainly involved in biological processes such as cell junction assembly

synapse organization

vesicle-mediated transport in synapse

dendrite development and cognition. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the differentially phosphorylated proteins were mainly enriched in pathways like insulin secretion

pancreatic secretion

glutamatergic synapse

endocytosis and long-term depression. Moreover

a protein-protein interaction (PPI) network with AGAP2

SYNGAP1

DRP2

DRP3 and PSD93 as the core proteins was formed.

Conclusion

Hypobaric hypoxia exposure can induce memory impairment in mice

which may be associated with the differential expression of phosphorylated proteins and changes of related pathways in the hippocampus of mice

and AGAP2

SYNGAP1

DRP2

DRP3 and PSD93 may be the key proteins during the process.

关键词

Keywords

references

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