[1]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(01):1-8.
 ZHONG Hongyu,WANG Lian,HAN Xiaoyu,et al.Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T+Itpr3tf/J mouse model of autism[J].J Third Mil Med Univ,2020,42(01):1-8.
点击复制

二甲双胍治疗改善新生期BTBR小鼠海马神经发生缺陷(/HTML )
分享到:

《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
42卷
期数:
2020年第01期
页码:
1-8
栏目:
神经科学
出版日期:
2020-01-15

文章信息/Info

Title:
Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T+Itpr3tf/J mouse model of autism
作者:
钟洪雨王炼韩晓雨许浩范晓棠
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
Author(s):
ZHONG Hongyu WANG Lian HAN Xiaoyu XU Hao FAN Xiaotang

Department of Military Cognitive Psychology, Faculty of Medical Psychology, Army Medical University (Third Military Medical University), Chongqing, 400038, China

关键词:
二甲双胍自闭症神经发生海马小鼠
Keywords:
metformin autism neurogenesis hippocampus mice
分类号:
R-332; R749.94; R977.15
文献标志码:
A
摘要:

目的研究生后早期二甲双胍治疗对BTBR T+Itpr3tf/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(n=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(P<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(P<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(P<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(P<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+Itpr3tf/J (BTBR) mouse model of autism. MethodsHealthy 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). ResultsOn 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 (P<0.05), while the numbers were obviously increased in BTBR+MET group than the C57+MET group (P<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 (P<0.05), the 2 kinds of cells were increased obviously in BTBR+MET group than the BTBR+NS group (P<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. ConclusionMET 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.

参考文献/References:

[1]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.
[2]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.
[3]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.
[4]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): 785-792. DOI:10.1007/s10654-019-00506-5.
[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.
[6]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.
[7]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.
[8]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.
[9]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.
[10]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.
[11]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.
[12]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.
[13]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.
[14]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.
[15]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.
[16]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.
[17]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.
[18]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.
[19]JULIANDI B, TANEMURA K, IGARASHI K, et al. Reduced adult hippocampal neurogenesis and cognitive impairments following prenatal treatment of the antiepileptic drug valproic acid[J]. Stem Cell Rep, 2015, 5(6): 996-1009. DOI:10.1016/j.stemcr.2015.10.012.
[20]RUSZNK K, CSEK 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.
[21]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.
[22]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.
[23]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.
[24]AHMED S, MAHMOOD Z, JAVED A, et al. Effect of metformin on adult 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.
[25]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.

相似文献/References:

[1]赵雪晴,赵聪敏,吴至凤,等.32例自闭症儿童的睡眠相关问题分析[J].第三军医大学学报,2009,31(22):2196.
 ZHAO Xue-qing,ZHAO Cong-min,WU Zhi-feng,et al.Analysis of sleep-related problems in 32 autistic children[J].J Third Mil Med Univ,2009,31(01):2196.
[2]秦利燕,戴旭芳.雷帕霉素对自闭症大鼠病症行为的改善作用[J].第三军医大学学报,2015,37(05):420.
 Qin Liyan,Dai Xufang.Role of rapamycin in improvement of autistic rats[J].J Third Mil Med Univ,2015,37(01):420.

更新日期/Last Update: 2020-01-07