Claudin 11 overexpression attenuates myelin ultrastructural damage and spatial cognitive impairment in neonatal mice following status epilepticus

WANG Jinglei; CEN Ling; CHENG Li; CHEN Hengsheng; LI Xue; JIANG Li

doi:10.16016/j.2097-0927.202604060

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Claudin 11 overexpression attenuates myelin ultrastructural damage and spatial cognitive impairment in neonatal mice following status epilepticus

Monographic Reports | 更新时间：2026-05-30

- Claudin 11 overexpression attenuates myelin ultrastructural damage and spatial cognitive impairment in neonatal mice following status epilepticus
- Journal of Army Medical University Vol. 48, Issue 10, Pages: 1326-1338(2026)
- 作者机构：
  
  重庆医科大学附属儿童医院神经内科，儿童少年健康与疾病国家临床医学研究中心，儿童发育疾病研究教育部重点实验室，重庆
- 作者简介：
  
  LI Xue，E-mail：xue.pedneurology@hospital.cqmu.edu.cn
  JIANG Li，E-mail：jiangli@email.com
- 基金信息：
  
  the Postdoctoral Science Found of Natural Science Foundation of Chongqing(CSTB2023NSCQ-BHX0115);the Postdoctoral Science Foundation of China(2024MD754033)
- DOI：10.16016/j.2097-0927.202604060
  CLC： R322.81;R341;R741
- Received：17 April 2026，
  
  Revised：2026-04-30，
  
  Accepted：03 May 2026，
  
  Published：30 May 2026
- 稿件说明：
移动端阅览
王静蕾，岑玲，程莉，等.过表达Claudin 11能减轻幼鼠惊厥持续状态后髓鞘超微结构损伤及空间认知障碍［J］.陆军军医大学学报，2026，48（10）：1326-1338.DOI：10.16016/j.2097-0927.202604060.

WANG J L，CEN L，CHENG L，et al.Claudin 11 overexpression attenuates myelin ultrastructural damage and spatial cognitive impairment in neonatal rats following status epilepticus［J］.J Army Med Univ，2026，48（10）：1326-1338.DOI：10.16016/j.2097-0927.202604060.
王静蕾，岑玲，程莉，等.过表达Claudin 11能减轻幼鼠惊厥持续状态后髓鞘超微结构损伤及空间认知障碍［J］.陆军军医大学学报，2026，48（10）：1326-1338.DOI：10.16016/j.2097-0927.202604060. DOI：

WANG J L，CEN L，CHENG L，et al.Claudin 11 overexpression attenuates myelin ultrastructural damage and spatial cognitive impairment in neonatal rats following status epilepticus［J］.J Army Med Univ，2026，48（10）：1326-1338.DOI：10.16016/j.2097-0927.202604060. DOI：

摘要

目的

儿童惊厥持续状态（status epilepticus， SE）常伴随脑白质髓鞘超微结构损伤。紧密连接蛋白11（Claudin 11）作为维持髓鞘径向紧密连接的关键分子，其功能缺失可显著降低神经传导速度并引发行为异常。基于此，本研究旨在探究过表达Claudin 11对小鼠SE后髓鞘结构损伤及空间认知功能的影响及其潜在保护作用。

方法

将18只21日龄雄性C57BL/6J小鼠（体质量9~11 g）按随机数字表法分为2组（

=9）：SE组［腹腔注射7.5 mg/kg红藻氨酸（kainic acid， KA， 2 mg/mL）以建立SE模型］和Ctrl组（腹腔注射等体积生理盐水）。建模后20 d，小鼠生长至41日龄，体质量16~26 g，开展指标检测：①采用Western blotting检测各组小鼠海马区Claudin 11及髓鞘碱性蛋白（myelin basic protein， MBP）表达水平（

=6/组）；②采用免疫荧光染色观察小鼠海马组织Claudin 11蛋白分布特征（

=3）。另选用16日龄雄性C57BL/6J小鼠，体质量6~9 g，共40只，采用随机数字表法将小鼠分为4组（

=10），CV+SE组：经侧脑室（intracerebroventricular，ICV）注射过表达Claudin 11腺相关病毒ScAAV2/9-CV-CLDN11-ZsGreen（病毒滴度：0.8×10¹³ vg/mL），病毒干预5 d后（21日龄）给予同剂量KA造模；NV+SE组：经ICV注射阴性空载体病毒ScAAV2/9-CMS-ZsGreen（病毒滴度：1.1×10¹³ vg/mL），干预5 d后（21日龄）给予同剂量KA造模；SE组：腹腔注射7.5 mg/kg KA（2 mg/mL）；Ctrl组：腹腔注射等量生理盐水。建模后20 d，小鼠生长至41日龄，体质量16~26 g时，开展指标检测：①采用透射电镜观察各组小鼠海马髓鞘超微结构（

=3/组）；②采用旷场实验、高架十字迷宫、Y迷宫及Morris水迷宫评估小鼠焦虑样行为及空间学习记忆能力（

=7）。

结果

①Western blotting检测显示，与Ctrl组比较，SE组小鼠海马中Claudin 11蛋白（

=0.007 7）与MBP表达均显著下降（

=0.033 6）；②免疫荧光结果显示，在Ctrl组和SE组中，Claudin 11/MBP双阳性细胞数量均显著高于Claudin 11/PDGFR-α及Claudin 11/Olig2双阳性细胞数（

0.000 1）。③透射电子显微镜观察发现，过表达Claudin 11后，CV+SE组髓鞘G-ratio值较SE组明显改善（

0.000 1）。④Morris水迷宫及Y迷宫实验结果显示，与SE组比较，CV+SE组小鼠Morris水迷宫逃避潜伏期显著缩短（

=0.021 2），Y迷宫自发交替率显著升高（

=0.006 7）；⑤旷场实验中心区域停留时间、中心区域进入次数百分比及高架十字迷宫开放臂停留时间百分比、开放臂进入次数百分比等差异无统计学意义。

结论

过表达Claudin 11可减轻小鼠SE后髓鞘结构损伤，并部分改善空间认知功能障碍，提示Claudin 11对SE后髓鞘损伤具有保护作用。

Abstract

Objective

Status epilepticus (SE) in children frequently induces ultrastructural damage to cerebral white matter myelin. Claudin 11

a key molecule maintaining radial tight junctions in myelin

whose deficiency significantly reduces nerve conduction velocity and causes behavioral abnormalities. This study investigated the effects of Claudin 11 overexpression on myelin structural integrity and spatial cognition post-SE in mice.

Methods

Eighteen 21-day-old male C57BL/6J mice

weighing 9 to 11 g

were randomly divided into two groups (

=9) using a random number table. The SE group received an intraperitoneal injection of 7.5 mg/kg kainic acid (KA

2 mg/mL) to induce SE

while the Ctrl gr

oup received an equal volume of normal saline. Twenty days after SE induction

when the mice reached 41 days of age and weighed 16 to 26 g

the following assessments were performed: ① Western blotting was used to detect Claudin 11 and myelin basic protein (MBP) protein expression levels in the hippocampus (

=6 per group); ② immunofluorescence staining was employed to observe the distribution of Claudin 11 protein in the hippocampus (

=3). An additional 40 male C57BL/6J mice

16-day-old and weighing 6 to 9 g

were randomly divided into 4 groups (

=10) using a random number table. The CV+SE group received an intracerebroventricular (ICV) injection of Claudin 11-overexpressing virus ScAAV2/9-CV-CLDN11-ZsGreen (viral titer: 0.8×10¹³ vg/mL)

and was given the same dose of KA 5 days after virus intervention (at 21 days of age). The NV+SE group received an ICV injection of negative control empty vector virus ScAAV2/9-CMS-ZsGreen (viral titer: 1.1×10¹³ vg/mL)

and was given the same dose of KA 5 days after intervention (at 21 days of age). Mice in the SE group and Ctrl group were housed under the same conditions until 21 days of age for the experiment; the SE group received an intraperitoneal injection of 7.5 mg/kg KA (2 mg/mL)

and the Ctrl group received an equal volume of normal saline. Twenty days after SE induction

when the mice reached 41 days of age and weighed 16 to 26 g

the following assessments were performed: ① transmission electron microscopy was used to observe the myelin sheath ultrastructure in the hippocampus (

=3); ② the open field test

elevated plus maze

Y-maze

and Morris water maze were used to evaluate anxiety-like behavior and spatial learning and memory ability (

=7).

Results

① Western blot analysis showed that compared with the Ctrl group

Claudin 11 protein (

=0.007 7) and MBP protein expression (

=0.033 6) in the hippocampus of the SE group wer

e significantly decreased. ② Immunofluorescence staining showed that

in both the Ctrl and SE groups

the number of Claudin 11/MBP double-positive cells was significantly higher than that of Claudin 11/PDGFR-α and Claudin 11/Olig2 double-positive cells (

0.000 1). ③ Transmission electron microscopy revealed that after Claudin 11 overexpression

the myelin G-ratio in the CV+SE group was significantly improved compared with the SE group (

0.000 1). ④ The Morris water maze and Y-maze tests showed that compared with the SE group

the escape latency in the Morris water maze was significantly shortened (

=0.021 2) and the spontaneous alternation rate in the Y-maze was significantly increased (

=0.006 7) in the CV+SE group. ⑤No statistically significant differences were observed in the time spent in the center zone

the percentage of entries into the center zone in the open field test

or the percentage of time spent and entries into the open arms in the elevated plus maze. Conclusion Claudin 11 overexpression attenuates SE-induced myelin damage and partially ameliorates spatial cognitive impairment

indicating its protective role against post-SE myelination deficits.

关键词

Keywords

references

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