Inhibition of GluA2-containing AMPA receptor endocytosis improves motor and cognitive functions in a rat model with traumatic brain injury

Zhu Lin; Xia Lei; Yuan Hao; Li Junjie; Xue Mengtong; Dai Chunfang; Shi Xiuyu; Yi Lilin; Dong Zhifang; Pang Yayan

doi:10.13406/j.cnki.cyxb.003617

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Inhibition of GluA2-containing AMPA receptor endocytosis improves motor and cognitive functions in a rat model with traumatic brain injury

Basic research | 更新时间：2025-10-23

- Inhibition of GluA2-containing AMPA receptor endocytosis improves motor and cognitive functions in a rat model with traumatic brain injury
- Journal of Chongqing Medical University Vol. 49, Issue 11, Pages: 1377-1384(2024)
- 作者机构：
  
  重庆医科大学附属儿童医院儿科研究所，国家儿童健康与疾病临床医学研究中心，儿童发育疾病研究教育部重点实验室，认知发育与学习记忆障碍转化医学重庆市重点实验室，重庆 400014
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003617
  CLC： R3
- Received：05 September 2024，
  
  Revised：2024-10-20，
  
  Accepted：28 October 2024，
  
  Published：28 November 2024
- 稿件说明：
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朱林,夏雷,袁浩,等.抑制AMPARs内吞可改善创伤性脑损伤大鼠的运动和认知功能[J].重庆医科大学学报,2024,49(11):1377-1384.

Zhu Lin,Xia Lei,Yuan Hao,et al.Inhibition of GluA2-containing AMPA receptor endocytosis improves motor and cognitive functions in a rat model with traumatic brain injury[J].Journal of Chongqing Medical University,2024,49(11):1377-1384.
朱林,夏雷,袁浩,等.抑制AMPARs内吞可改善创伤性脑损伤大鼠的运动和认知功能[J].重庆医科大学学报,2024,49(11):1377-1384. DOI： 10.13406/j.cnki.cyxb.003617.

Zhu Lin,Xia Lei,Yuan Hao,et al.Inhibition of GluA2-containing AMPA receptor endocytosis improves motor and cognitive functions in a rat model with traumatic brain injury[J].Journal of Chongqing Medical University,2024,49(11):1377-1384. DOI： 10.13406/j.cnki.cyxb.003617.

摘要

目的

研究抑制含GluA2亚基的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors，AMPARs）的内吞对创伤性脑损伤（traumatic brain injury，TBI）大鼠模型运动和认知能力的作用及相关机制。

方法

构建中度TBI模型大鼠，分为Sham（仅开放颅窗）组，saline（生理盐水处理）组，scr-GluA2

（对照肽scrambled Tat-GluA2

处理）组和GluA2

（实验肽Tat-GluA2

处理）组，通过改良神经功能评分（Mahmood’s method neurological severity score，mNSS）及抓力实验检测大鼠运动及神经功能改善情况，之后用新物体实验和水迷宫实验评估大鼠的探索能力与空间学习记忆能力。后期通过Western blot分别检测海马体的突触蛋白和总蛋白中AMPARs表达情况的变化。

结果

mNSS及抓力实验显示：随时间推移，GluA2

组的神经功能状态（

=0.013）及抓力（

0.001）相较于saline组明显改善。新物体实验显示：GluA2

组的接触次数（0.60±0.02，

0.01）及接触时间（0.57±0.03，

=0.011）与scr-GluA2

组相比明显增加（

0.01，

=0.010）。水迷宫结果显示：与scr-GluA2

组相比，GluA2

组（21.43±1.76）的学习（

0.001）与记忆（

=0.037）能力提高。Western blot显示：与对照组相比，GluA2

治疗（0.98±0.03，

=0.981 vs. Sham组，

=0.025 vs. saline组，

=0.025 vs. scr-GluA2

组）可特异性提高海马中GluA2的含量。

结论

AMPARs内吞抑制剂，如Tat-GluA2

可通过提高大鼠海马体中GluA2的含量来修复TBI引起的运动和认知功能受损。

Abstract

Objective

To investigate the effects of inhibition of GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor（AMPAR） endocytosis on motor and cognitive functions in a rat model with traumatic brain injury（TBI） and related mechanisms.

Methods

The model rats with moderate TBI were established and divided into the Sham group （with open cranial window only），saline group（treated with normal saline），scr-GluA2

group （treated with the control peptide scrambled Tat-GluA2

），and GluA2

group（treated with the test peptide Tat-GluA2

）. The improvement in motor and neurological functions of rats was measured by the Mahmood’s method neurological severity score（mNSS） and grip strength test. Then，the exploration ability and spatial learning and memory ability of rats were assessed by the new object experiment and water maze experiment. The change in AMPAR expression of synaptic and total proteins in the hippocampus was measured by Western blot.

Results

The mNSS and grip strength test showed that the neurofunction status（

=0.013） and grip strength（

0.001） of the GluA2

group improved significantly over time compared with the saline group. The new object experiment showed that the number of contacts （0.60±0.02，

0.01） and contact time（0.57±0.03，

=0.011） of the GluA2

group were significantly increased compared with the scr-GluA2

group（

0.01，

=0.010）. The water maze experiment results showed that the learning（

0.001） and memory ability（

=0.037）

were improved in the GluA2

group （21.43±1.76） compared with the scr-GluA2

group. Western blot revealed that the content of GluA 2 in the hippocampus was specifically increased after treatment with GluA2

（0.98±0.03，

=0.981 vs. Sham，

=0.025 vs. saline，

=0.025 vs. scr-GluA2

）.

Conclusion

AMPAR endocytosis inhibitors，such as Tat-GluA2

，repair the impaired motor and cognitive function induced by TBI by increasing the content of GluA2 in the rat hippocampus.

关键词

Keywords

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