雌激素β受体激动剂改善自闭症模型小鼠的社交缺陷

张瑞宇; 刘天曜; 肖锐; 范晓棠

doi:10.16016/j.1000-5404.201811078

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雌激素β受体激动剂改善自闭症模型小鼠的社交缺陷

基础医学 | 更新时间：2026-01-09

- 雌激素β受体激动剂改善自闭症模型小鼠的社交缺陷
- Estrogen receptor β agonist ameliorates social deficits in a mouse model of autism
- 第三军医大学学报 2019年41卷第6期页码：507-513
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)医学心理系军事认知心理学教研室
- 作者简介：
  
  [范晓棠，E-mail：fanxiaotang2005@163.com FAN Xiaotang, E-mail:fanxiaotang2005@163.com
- 基金信息：
  
  国家自然科学基金面上项目(31871043)
- DOI：10.16016/j.1000-5404.201811078
  中图分类号： R-332; R749.91; R977.12
- 收稿：2018-11-12，
  
  修回：2018-12-24，
  
  纸质出版：2019-03-30
- 稿件说明：
移动端阅览
张瑞宇, 刘天曜, 肖锐, 等. 雌激素β受体激动剂改善自闭症模型小鼠的社交缺陷[J]. 第三军医大学学报, 2019,41(6):507-513.

Ruiyu ZHANG, Tianyao LIU, Rui XIAO, et al. Estrogen receptor β agonist ameliorates social deficits in a mouse model of autism[J]. Journal of Third Military Medical University, 2019, 41(6): 507-513.
张瑞宇, 刘天曜, 肖锐, 等. 雌激素β受体激动剂改善自闭症模型小鼠的社交缺陷[J]. 第三军医大学学报, 2019,41(6):507-513. DOI： 10.16016/j.1000-5404.201811078.

Ruiyu ZHANG, Tianyao LIU, Rui XIAO, et al. Estrogen receptor β agonist ameliorates social deficits in a mouse model of autism[J]. Journal of Third Military Medical University, 2019, 41(6): 507-513. DOI： 10.16016/j.1000-5404.201811078.

摘要

目的

探讨雌激素β受体特异性激动剂ly3201对自闭症模型BTBR小鼠的行为改善作用。

方法

将健康同窝C57BL/6J(C57)、BTBR小鼠分为4组：C57生理盐水组、C57药物处理组、BTBR生理盐水组、BTBR药物处理组；小鼠生后2 d，药物处理组腹腔注射雌激素β受体激动剂ly3201(1.6 mg/kg)，生理盐水组腹腔注射等量生理盐水；于生后14 d采用荧光定量PCR和免疫组化检测各组小鼠皮层与海马内雌激素β受体的表达；于小鼠2月龄进行自闭症相关行为学检测。

结果

生后14 d，BTBR生理盐水组皮层与海马内雌激素β受体的表达显著低于C57生理盐水组(

0.05)，而ly3201处理则上调了C57与BTBR小鼠皮层及海马内雌激素β受体的表达(

0.01)。在三箱社交实验中，BTBR药物处理组小鼠在小鼠箱体停留时间大于在物体箱体中停留时间(

0.05)，对小鼠的嗅探时间大于对物体的嗅探时间(

0.05)；并且统计箱体时间(

0.01)和嗅探时间(

0.01)偏好系数也显示BTBR药物处理组表现出对小鼠的明显偏好；在交互实验中，BTBR药物处理组鼻对鼻嗅探时间(

0.05)、鼻对会阴嗅探时间(

0.05)明显多于BTBR生理盐水组，而其对箱体探索时间明显少于BTBR生理盐水组(

0.05)。

结论

雌激素β受体激动剂ly3201激活海马与皮层内源性雌激素β受体的表达，显著改善BTBR自闭症模型小鼠的社交缺陷。

Abstract

Objective

To explore the therapeutic effect of estrogen receptor β agonist ly3201 on autism-like behaviors in BTBR mice.

Methods

Healthy neonatal (2 days old) C57BL/6J(C57) and BTBR littermate mice were both divided into 2 groups and subjected to intraperitoneal injections of estrogen receptor β agonist ly3201 at the dose of 1.6 mg/kg or normal saline of an equivalent volume. We measured the expression levels of estrogen receptor β in the cerebral cortex and hippocampus of the mice on day 14 after birth with immunohistochemistry and real-time PCR

and tested the mice for autism-like behaviors at 2 months of age.

Results

At 14 d after birth

the expression levels of estrogen receptor β in the cerebral cortex and hippocampus were significantly lower in BTBR mice than in C57 mice (

0.05)

and treatment with ly3201 obviously enhanced estrogen receptor β expression in both BTBR and C57 mice (

0.01). In the three-chambered social test

BTBR mice with ly3201 treatment spent significantly longer time in the chamber with other mice than in the chamber with a new object (

0.05); they also spent significantly longer time for exploratory sniffing of other mice than of the new object (

0.05). In the male-female reciprocal social interaction test

compared with the saline-treated mice

BTBR mice with ly3201 treatment exhibited longer time of nose-to-nose sniffing (

0.05) and anogenital sniffing (

0.05) with a significantly reduced time for cage exploration (

0.05).

Conclusion

Estrogen receptor β agonist ly3201 activates the expression of endogenous estrogen receptor in the hippocampus and cortex to alleviate social deficits in BTBR mice.

关键词

Keywords

references

CHEN J A, PEÑAGARIKANO O, BELGARD T G, et al . The emerging picture of autism spectrum disorder:genetics and pathology[J ] . Annu Rev Pathol, 2015, 10:111-144. DOI:10.1146/annurev-pathol-012414-040405.

GOINES P E, ASHWOOD P. Cytokine dysregulation in autism spectrum disorders (ASD):possible role of the environment[J]. Neurotoxicol Teratol, 2013, 36:67-81. DOI:10.1016/j.ntt.2012.07.006.

VARGAS D L, NASCIMBENE C, KRISHNAN C, et al . Neuroglial activation and neuroinflammation in the brain of patients with autism[J ] . Ann Neurol, 2005, 57(1):67-81. DOI:10.1002/ana.20315.

MORGAN J T, CHANA G, PARDO C A, et al . Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism[J ] . Biol Psychiatry, 2010, 68(4):368-376. DOI:10.1016/j.biopsych.2010.05.024.

YOUNG A M, CAMPBELL E, LYNCH S, et al . Aberrant NF-kappaB expression in autism spectrum condition:A mechanism for neuroinflammation[J ] . Front Psychiatry, 2011, 2:27. DOI:10.3389/fpsyt.2011.00027.

BERKEL S, ELTOKHI A, FR HLICH H, et al . Sex hormones regulate SHANK expression[J ] . Front Mol Neurosci, 2018, 11:337. DOI:10.3389/fnmol.2018.00337.

HOFFMAN E J, TURNER K J, FERNANDEZ J M, et al . Estrogens suppress a behavioral phenotype in zebrafish mutants of the autism risk gene, CNTNAP2[J ] . Neuron, 2016, 89(4):725-733. DOI:10.1016/j.neuron.2015.12.039.

FILICE F, LAUBER E, VÖRCKEL K J, et al . 17-β estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms[J ] . Mol Autism, 2018, 9:15. DOI:10.1186/s13229-018-0199-3.

KREZEL W, DUPONT S, KRUST A, et al . Increased anxiety and synaptic plasticity in estrogen receptor beta -deficient mice[J ] . Proc Natl Acad Sci USA, 2001, 98(21):12278-12282. DOI:10.1073/pnas.221451898.

FAN X T, WARNER M, GUSTAFSSON J A. Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons[J]. Proc Natl Acad Sci USA, 2006, 103(51):19338-19343. DOI:10.1073/pnas.0609663103.

ZOU Y L, LU Q M, ZHENG D, et al . Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERβ suppression in the amygdala[J ] . Mol Autism, 2017, 8:46. DOI:10.1186/s13229-017-0159-3.

XIE W G, GE X H, LI L, et al . Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation[J ] . Mol Autism, 2018, 9:43. DOI:10.1186/s13229-018-0225-5.

CRIDER A, THAKKAR R, AHMED A O, et al . Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects[J ] . Mol Autism, 2014, 5(1):46. DOI:10.1186/2040-2392-5-46.

CRIDER A, NELSON T, DAVIS T, et al . Estrogen receptor β agonist attenuates endoplasmic reticulum stress-induced changes in social behavior and brain connectivity in mice[J ] . Mol Neurobiol, 2018, 55(9):7606-7618.DOI:10.1007/s12035-018-0929-8.

AMODEO D A, RIVERA E, COOK E H JR, et al . 5HT2A receptor blockade in dorsomedial striatum reduces repetitive behaviors in BTBR mice[J ] . Genes Brain Behav, 2017, 16(3):342-351. DOI:10.1111/gbb.12343.

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