二甲双胍治疗改善新生期BTBR小鼠海马神经发生缺陷

钟洪雨; 王炼; 韩晓雨; 许浩; 范晓棠

doi:10.16016/j.1000-5404.201907206

您当前的位置：

首页 >

文章列表页 >

二甲双胍治疗改善新生期BTBR小鼠海马神经发生缺陷

神经科学 | 更新时间：2026-01-09

- 二甲双胍治疗改善新生期BTBR小鼠海马神经发生缺陷
- Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T⁺Itpr3^tf/J mouse model of autism
- 第三军医大学学报 2020年42卷第1期页码：1-8
- 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.comFAN 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.1000-5404.201907206
  中图分类号： R-332;R749.94;R977.15
- 收稿：2019-07-26，
  
  修回：2019-08-31，
  
  纸质出版：2020-01-15
- 稿件说明：
移动端阅览
钟洪雨, 王炼, 韩晓雨, 等. 二甲双胍治疗改善新生期BTBR小鼠海马神经发生缺陷[J]. 第三军医大学学报, 2020,42(1):1-8.

Hongyu ZHONG, Lian WANG, Xiaoyu HAN, et al. Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T⁺Itpr3^tf/J mouse model of autism[J]. Journal of Third Military Medical University, 2020, 42(1): 1-8.
钟洪雨, 王炼, 韩晓雨, 等. 二甲双胍治疗改善新生期BTBR小鼠海马神经发生缺陷[J]. 第三军医大学学报, 2020,42(1):1-8. DOI： 10.16016/j.1000-5404.201907206.

Hongyu ZHONG, Lian WANG, Xiaoyu HAN, et al. Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T⁺Itpr3^tf/J mouse model of autism[J]. Journal of Third Military Medical University, 2020, 42(1): 1-8. DOI： 10.16016/j.1000-5404.201907206.

摘要

目的

研究生后早期二甲双胍治疗对BTBR T

Itpr3

/J (BTBR)自闭症模型小鼠海马神经发生的影响。

方法

利用随机数字表法将新生健康C57BL/6J (C57)、BTBR小鼠分为4组(

=5):C57生理盐水组、C57药物处理组、BTBR生理盐水组、BTBR药物处理组。生后7 d(postnatal day 7，P7)，两药物处理组予以二甲双胍(200 mg/kg)腹腔注射，每天1次，共计8次；C57及BTBR生理盐水组予以等量的生理盐水。于P14最后1次二甲双胍注射2 h后

收取脑标本进行免疫荧光染色，检测海马齿状回5-溴脱氧尿嘧啶核苷(5-bromo-2’-deoxyuridine，BrdU)、Ki67、Sox2/GFAP及Prox1的表达。

结果

在P14时，BTBR生理盐水组海马齿状回的BrdU及Ki67标记的增殖神经细胞数量比C57生理盐水组显著减少(

0.05)，而BTBR药物处理组BrdU及Ki67阳性细胞均比BTBR生理盐水组明显增多(

0.05)；BTBR生理盐水组SOX2/GFAP标记的神经干细胞和Prox1标记的新生神经元数量均比C57生理盐水组显著减少(

0.05)，而BTBR药物处理组上述两种细胞数量比BTBR生理盐水组明显增多(

0.05)。而二甲双胍早期干预并没有对C57小鼠海马神经发生产生显著影响，C57生理盐水组与C57药物处理组BrdU、Ki67、Sox2/GFAP及Prox1的表达差异无统计学意义。

结论

生后早期二甲双胍治疗显著改善BTBR小鼠海马神经发生缺陷，促进海马齿状回神经元及神经干细胞增殖。

Abstract

Objective

To investigate the effects of metformin (MET) treatment during early postnatal period on hippocampal neurogenesis of neonatal BTBR T

Itpr3

/J (BTBR) mouse model of autism.

Methods

Healthy C57BL/6J (C57) and BTBR male pups were randomly divided into C57 normal saline group (C57+NS)

C57 MET treatment group (C57+MET)

BTBR+NS

and BTBR+MET group

with 5 animals in each group. From postnatal day 7 (P7) to P14

MET (200 mg/kg) or normal saline (same volume of sterile saline solution) were intraperitoneally injected into the corresponding mice

once per day. In 2 h after the last injection on P14

all mice were sacrificed

and the brains were collected and sliced coronally. Fluorescent immunostaining was performed to detect the expression of 5-bromo-2'-deoxyuridine (BrdU)

Ki67

Sox2/GFAP and Prox1 in the dentate gyrus (DG).

Results

On P14

the numbers of BrdU-labeled cells and Ki67-labeled cells were significantly less in the DG of BTBR+NS group than the C57+NS group (

0.05)

while the numbers were obviously increased in BTBR+MET group than the C57+MET group (

0.05). Although there were remarkably less Sox2 and GFAP double-positive cells (neural stem cells) and Prox1-positive cells (newborn neurons) in BTBR+NS group than the C57+NS group (

0.05)

the 2 kinds of cells were increased obviously in BTBR+MET group than the BTBR+NS group (

0.05). However

MET treatment showed no effect on the hippocampal neurons

and there were no significant differences in the numbers of BrdU-

Ki67-

Sox2/GFAP- and Prox1-labeled cells between the C57+MET and C57+NS groups.

Conclusion

MET treatment in early postnatal period significantly improves the defects of hippocampal neurogenesis

and promotes the proliferation of hippocampal DG neurons and neural stem cells in BTBR mice.

关键词

Keywords

references

CURRAIS A, FARROKHI C, DARGUSCH R, et al . Dietary glycemic index modulates the behavioral and biochemical abnormalities associated with autism spectrum disorder[J ] . Mol Psychiatry, 2016, 21(3): 426-436. DOI:10.1038/mp.2015.64.

CHRISTENSEN D L, MAENNER M J, BILDER D, et al . Prevalence and characteristics of autism spectrum disorder among children aged 4 years—early autism and developmental disabilities monitoring network, seven sites, United States, 2010, 2012, and 2014[J ] . MMWR Surveill Summ, 2019, 68(2): 1-19. DOI:10.15585/mmwr.ss6802a1.

CARPITA B, MUTI D, DELL'OSSO L. Oxidative stress, maternal diabetes, and autism spectrum disorders[J]. Oxid Med Cell Longev, 2018, 2018: 3717215. DOI:10.1155/2018/3717215.

LEE B K, GROSS R, FRANCIS R W, et al . Birth seasonality and risk of autism spectrum disorder[J ] . Eur J Epidemiol, 2019, 34(8): 785-79 2. DOI:10.1007/s10654-019-00506-5.

CASTILLA-ORTEGA E, SERRANO A, BLANCO E, et al . A place for the hippocampus in the cocaine addiction circuit: Potential roles for adult hippocampal neurogenesis[J ] . Neurosci Biobehav Rev, 2016, 66: 15-32. DOI:10.1016/j.neubiorev.2016.03.030.

GILBERT J, MAN H Y. Fundamental elements in autism: from neurogenesis and neurite growth to synaptic plasticity[J]. Front Cell Neurosci, 2017, 11: 359. DOI:10.3389/fncel.2017.00359.

GROEN W B, BUITELAAR J K, VAN DER GAAG R J, et al . Pervasive microstructural abnormalities in autism: a DTI study[J ] . J Psychiatry Neurosci, 2011, 36(1): 32-40. DOI:10.1503/jpn.090100.

WEGIEL J, KUCHNA I, NOWICKI K, et al . The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes[J ] . Acta Neuropathol, 2010, 119(6): 755-770. DOI:10.1007/s00401-010-0655-4.

CHEN Z F, LI X, ZHOU J J, et al . Accumulated quiescent neural stem cells in adult hippocampus of the mouse model for the MECP2 duplication syndrome[J ] . Sci Rep, 2017, 7: 41701. DOI:10.1038/srep41701.

LIU Y H, LAI W S, TSAY H J, et al . Effects of maternal immune activation on adult neurogenesis in the subventricular zone-olfactory bulb pathway and olfactory discrimination[J ] . Schizophr Res, 2013, 151(1/2/3): 1-11. DOI:10.1016/j.schres.2013.09.007.

ZHANG R Y, CAI Y L, XIAO R, et al . Human amniotic epithelial cell transplantation promotes neurogenesis and ameliorates social deficits in BTBR mice[J ] . Stem Cell Res Ther, 2019, 10(1): 153. DOI:10.1186/s13287-019-1267-0.

MOUSAVI S M, NIAZMAND S, HOSSEINI M, et al . Beneficial effects of teucrium polium and metformin on diabetes-induced memory impairments and brain tissue oxidative damage in rats[J ] . Int J Alzheimers Dis, 2015, 2015: 493729. DOI:10.1155/2015/493729.

WANG L, CAI Y L, FAN X T. Metformin administration during early postnatal life rescues autistic-like behaviors in the BTBR T+ Itpr3tf/J mouse model of autism[J]. Front Behav Neurosci, 2018, 12: 290. DOI:10.3389/fnbeh.2018.00290.

OU Z R, KONG X J, SUN X D, et al . Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice[J ] . Brain Behav Immun, 2018, 69: 351-363. DOI:10.1016/j.bbi.2017.12.009.

APPLE D M, SOLANO-FONSECA R, KOKOVAY E. Neurogenesis in the aging brain[J]. Biochem Pharmacol, 2017, 141: 77-85. DOI:10.1016/j.bcp.2017.06.116.

GROEN W, TELUIJ M, BUITELAAR J, et al . Amygdala and Hippocampus enlargement during adolescence in autism[J ] . J Am Acad Child Adolesc Psychiatry, 2010, 49(6): 552-560. DOI:10.1016/j.jaac.2009.12.023.

COPE E C, BRIONES B A, BROCKETT A T, et al . Immature neurons and radial glia but not astrocytes or microglia, are altered in adult Cntnap2 and Shank3 mice, models of autism[J ] . eNeuro, 2016, 3(5). DOI:10.1523/ENEURO.0196-16.2016.

ZENG Q H, LONG Z M, FENG M, et al . Valproic acid stimulates hippocampal neurogenesis via activating the wnt/β-catenin signaling pathway in the APP/PS1/nestin-GFP triple transgenic mouse model of Alzheimer's disease[J ] . Front Aging Neurosci, 2019, 11: 62. DOI:10.3389/fnagi.2019.00062.

JULIANDI B, TANEMURA K, IGARASHI K, et al . Reduced adult hippocampal neurogenesis and cognitive impairments following prenatal treatmen t of the antiepileptic drug valproic acid[J ] . Stem Cell Rep, 2015, 5(6): 996-1009. DOI:10.1016/j.stemcr.2015.10.012.

RUSZNÁK K, CSEKÖ K, VARGA Z, et al . Long-term stress and concomitant marijuana smoke exposure affect physiology, behavior and adult hippocampal neurogenesis[J ] . Front Pharmacol, 2018, 9: 786. DOI:10.3389/fphar.2018.00786.

CAI Y L, ZHONG H Y, LI X, et al . The liver X receptor agonist TO901317 ameliorates behavioral deficits in two mouse models of autism[J ] . Front Cell Neurosci, 2019, 13: 213. DOI:10.3389/fncel.2019.00213.

ODDI D, SUBASHI E, MIDDEI S, et al . Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome[J ] . Neuropsychopharmacology, 2015, 40(5): 1113-1122. DOI:10.1038/npp.2014.291.

VUILLERMOT S, LUAN W, MEYER U, et al . Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation[J ] . Mol Autism, 2017, 8: 9. DOI:10.1186/s13229-017-0125-0.

AHMED S, MAHMOOD Z, JAVED A, et al . Effect of metformin on adul t hippocampal neurogenesis: comparison with donepezil and links to cognition[J ] . J Mol Neurosci, 2017, 62(1): 88-98. DOI:10.1007/s12031-017-0915-z.

TANOKASHIRA D, KURATA E, FUKUOKAYA W, et al . Metformin treatment ameliorates diabetes-associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1[J ] . FEBS Open Bio, 2018, 8(7): 1104-1118. DOI:10.1002/2211-5463.12436..

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

柴胡口服液改善成年BTBR自闭症小鼠海马神经发生及短期记忆缺陷

米诺环素可以改善新生期BTBR小鼠海马神经发生缺陷

番茄红素改善BTBR小鼠社交障碍及降低海马炎症

星形胶质细胞中LXRβ缺失对生后早期海马神经发生的影响

海马PGC-1α对小鼠抑郁样行为及海马各亚区星形胶质细胞数量的影响