International Journal of Psychiatry and Neurology
Vol.3 No.03(2014), Article ID:14212,6 pages
DOI:10.12677/IJPN.2014.33003

BTBR T~(+)tf/J Mouse: An Ideal Animal Model for Autism Spectrum Disorders

Bing Wang, Lin Du, Ling Shan, Honghua Li, Junyan Feng, Feiyong Jia

Division of Pediatric Neurorehabilitation of First Hospital of Jilin University, Changchun

Email: erkekangfujia@163.com

Copyright © 2014 by authors and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

Received: Jul. 15th, 2014; revised: Aug. 10th, 2014; accepted: Aug. 25th, 2014

ABSTRACT

Autism spectrum disorder (ASD) is a complex heterogeneous of neuro developmental disorders which originate from the early childhood with the core symptoms of impaired communication, social impairments, and restricted and repetitive behaviors and interests. Research has so far indicated that ASD exists genetic basis and may be induced bursting out under certain conditions which include the factors such as maternal immunity, autoimmune disorder, natural environment etc., and children with ASD exist cerebral dysplasia. However, the pathogenesis of ASD is still inadequately understood which needs us to make further study on it. Animal model can be used as an important basis for evaluating the experimental results. Therefore, to establish an appropriate ASD model is the foundation of experiment. Since ASD is a kind of disease caused by many factors and may include many kinds of pathogenetic mechanisms, whether we can choose an animal model which can accurately replicate the pathological and clinical features of ASD is of great significance for the further research of ASD. BTBR T~(+)tf/J (BTBR for short) mice is a kind of inbred strain mice which not only possesses the core symptoms such as reduction of social intercourse, lack of ultrasonic on social occasions and severe repeated grooming behavior, but also possesses cerebral dysplasia and immune biochemical index abnormalities similar to ASD. Based on this, BTBR mice is currently the ideal model for the study of autism. The aim of this article is to summarize the relationship between BTBR mice and ASD.

Keywords:ASD, Animal Model, BTBR Mice

BTBR T~(+)tf/J小鼠:孤独症谱系障碍理想的
动物模型

王  冰,杜  琳,单  玲,李洪华,冯俊燕,贾飞勇

吉林大学第一医院小儿神经康复科,长春

Email: erkekangfujia@163.com

收稿日期:2014年7月15日;修回日期:2014年8月10日;录用日期:2014年8月25日

摘  要

孤独症谱系障碍(autism spectrum disorders, ASD)是一组起源于儿童早期的以社会交往交流障碍和重复刻板的行为和兴趣为主要症状的神经发育性障碍。目前研究表明,ASD存在遗传基础,并在一定的环境诱导下发病,包括母体免疫因素、自身免疫紊乱及自然环境因素等,且存在脑发育的异常。但ASD的病因及发病机制尚不完全明确,尚需我们进一步研究。动物模型是评价实验结果的重要依据,确立合适的ASD模型是实验的基础。由于ASD是多因素引起的、可能涉及多种病理机制的疾病,能否选择精准复制ASD病理特征和临床症状的动物模型对ASD的深入研究具有重大意义。BTBR T~(+)tf/J (简称BTBR)小鼠是一种近交系小鼠,它不仅具有ASD的核心症状:社交减少、社交场合中发出的超声波少、重度的重复理毛行为;同时还具备与ASD类似的脑发育异常以及免疫生化指标异常。因此,BTBR小鼠是目前研究自闭症的理想模型,本文就BTBR小鼠与ASD的关系进行总结。

关键词

孤独症谱系障碍,动物模型,BTBR小鼠

1. 引言

实验动物根据遗传的均一性、敏感性和一致性,分为近交系动物、封闭群动物、杂交型动物。其中近交系动物是经过20代以上连续全同胞或亲子交配而得,品系内所有个体都可追溯到起源于第20代或以后代数的一对共同祖先的动物群,具有稳定的基因型,个体之间反应一致,对实验的反应也高度一致,因此,实验数据标准差较小,在实验中实验组和对照组都只需少量的动物。BTBR小鼠就是一种近交系小鼠,具有稳定的基因型,能稳定的表现出社会交往交流障碍和重复刻板行为和兴趣等ASD样行为,以及ASD类似的脑发育异常以及免疫生化指标异常。本文通过行为、脑发育、免疫生化三个方面对BTBR小鼠与ASD关系进行阐述。

2. BTBR小鼠行为学与ASD关系

由于病因及发病机制不明,目前ASD的定义是行为标准,故诊断依据主要为行为症状,其核心症状主要有:社会交往障碍、言语交流障碍、兴趣狭窄及刻板行为;除此之外,可以伴随学习障碍及注意力缺陷等症状[1] 。因此,ASD小鼠模型的选用需要大量观察小鼠的具体行为是否具备ASD的各种诊断症状。行为学家经过大量细致的观察,总结出小鼠一系列社会交往、交流以及重复刻板的行为的表现[2] -[8] ,包括:社交方法、社会互动的异常和嗅觉沟通的异常,超声波发声的异常,刻板运动(如旋转和重复跳跃),刻板行为(如自我理毛和挖掘)等[9] 。研究人员对十余种近交系小鼠进行行为学分析,发现A/J小鼠、BALB/cByJ小鼠、BTBR小鼠和129S1/SvImJ小鼠表现出低水平的社交行为,而C57BL/6小鼠(简称C57)和FVB/AntJ (简称FVB)小鼠是一种具有正常社交行为的标准鼠系。其中BTBR小鼠不但存在低水平的社交行为,而且在水迷宫中也表现出对固定变化模式的坚持,因此认为BTBR小鼠有可能是一种ASD的动物模型[10] -[12] ,从而进一步对其进行一些列行为学检测。

三室装置是用来检测小鼠社交行为的经典装置,主要是在一个被分隔成三个区域的透明装置中的不同区域分别放置陌生小鼠和新奇物体,观察不同鼠系小鼠对物体和同类的关注程度。研究表明BTBR小鼠对新奇物体的关注度超过对陌生小鼠的兴趣,这与C57小鼠的正常社交行为完全相反[12] -[14] ,提示BTBR小鼠存在社会行为缺陷。

在不同环境中BTBR小鼠发出的超声波也明显减少[15] 。对C57、FVB及BTBR三种近交系雄性小鼠对陌生雌鼠的出现(第一阶段)、消失(第二阶段)、再出现(第三阶段)所发出的超声波进行检测,在第一阶段三种近交系雄鼠均发出超声波,而当第三阶段雌鼠再次出现时,发出与第一阶段接近的超声波数量。其中BTBR雄鼠在这三个环节中所发出的超声波较其他两系明显减少[16] 。

除了社会交往受限及发声减少,BTBR小鼠还表现出咬槽癖的狭窄兴趣[17] 和自我理毛行为的增加[13] [18] [19] 。与FVB小鼠不同的是,BTBR小鼠在洞板探索试验中,无论洞板下的嗅觉刺激物及位置如何更换,BTBR小鼠都明显的喜欢睡在角落的洞口处[20] 。

研究人员进一步对BTBR小鼠和C57小鼠进行不同空间逆转学习试验(100%反馈和80/20概率反馈),结果表明,在100%反馈逆转学习试验中,两种小鼠表现相似;然而在80/20概率反馈逆转学习试验中,BTBR小鼠却表现出明显的学习缺陷,并出现理石埋藏和自我理毛行为。提示BTBR小鼠不单具备ASD患者表现出的刻板行为,还能体现其内在的“坚持相同”的思维方式[21] 。因此,BTBR小鼠不仅能做为研究ASD核心行为的动物模型,还能够作为研究ASD行为灵活度受限的动物模型。

3. BTBR小鼠脑结构及神经递质与ASD关系

纹状体是基底神经节的主要组成部分,包括豆状核和尾状核,主要参与维持机体的固定姿势,研究表明,ASD的刻板重复行为与纹状体发育异常相关。研究人员对99例高功能自闭症患者进行头部核磁扫描,发现与刻板重复行为相关的纹状体区域主要位于尾状核头,其体积随自闭症患儿年龄增长儿增加[22] 。此外,一系列的临床研究也发现ASD患儿胼胝体缩小和变薄[23] [24] 。对BTBR小鼠进行核磁扫描和弥散成像,并以另外两种高社交能力和少有自我理毛行为的标准鼠系C57小鼠和FVB小鼠作对照,以期发现与BTBR小鼠刻板行为有关的脑功能区域。结果提示存在刻板行为(重复自我理毛行为)的BTBR小鼠纹状体体积较C57小鼠、FVB小鼠增大,且纹状体体积与小鼠自我理毛行为时间的长短呈正相关。另外,BTBR小鼠脑内胼胝体发育不全也已经被报道[25] 。

硫酸乙酰肝素(heparan sulfate, HS)是一类具电负性的线性多糖,存在于所有动物组织细胞及胞外基质中,能与多种生长因子、趋化因子、形态发生素、酶等蛋白发生相互作用,影响多种信号通路,参与脑的形成以及轴突的导向,是正常脑发育的基础[26] 。HS在海马的生物活性以及中枢神经系统的学习及记忆功能中也起到重要作用。Pearson等通过对儿童ASD患者进行尸检,发现脑组织中侧脑室室管膜下区的HS含量较同龄正常对照儿童明显减少[27] 。研究报道HS合成的限速酶基因EXT1敲除小鼠也表现出了社会交往减少、刻板重复行为和发声障碍等一系列ASD症状[28] 。儿童如果EXT1外显子9和11的突变也可导致ASD的产生[29] 。因此,HS可能与ASD的发生密切相关。研究人员对BTBR小鼠脑组织进行研究,发现BTBR小鼠脑内HS水平较其他非ASD小鼠降低,外周组织中硫含量下降,脑内的N端硫化的HS含量显著下降[30] 。

乙酰胆碱是一种重要的神经递质,日本科学家对ASD患者进行脑功能检测发现,自闭症患者大脑中乙酰胆碱含量比正常水平平均大约低30%[31] 。而Stephanie等人用自动触屏测试装置对BTBR小鼠进行5选择序列反应时间任务测试(5-CSRTT),同时检测与5-CSRTT水平相关的脑功能区域——前额叶皮质基底细胞外一组细胞的神经递质水平,结果提示BTBR小鼠发现短暂刺激的准确性降低,基底细胞外乙酰胆碱水平降低,犬尿喹啉酸水平升高[32] 。准确的完成5-CSRTT需要完整的胆碱能传递,而BTBR小鼠缺少乙酰胆碱,从而引起5-CSRTT准确性下降。

4. BTBR小鼠免疫生化水平与ASD关系

越来越多的证据提示免疫因素在ASD的发病中起到重要作用,其中母体免疫激活和体内免疫紊乱目前被认为是ASD发病的重要环境因素。

母体免疫激活是指由于母体在怀孕期间感染病原体后(病毒、细菌、寄生虫等),对入侵体内的病原体进行免疫应答,产生大量的细胞因子和抗体,从而对胎儿的脑发育产生影响。而ASD患儿母亲血清及羊水中明显增高的细胞因子和趋化因子水平[33] [34] ,异卵双生子的ASD发病率远高于非双生子的兄弟[35]  36] ,均提示母体内环境因素对ASD的发病起到重要作用。而用Poly I:C刺激孕期的BTBR小鼠和C57小鼠后,仅有BTBR小鼠体内存在持续的免疫紊乱,C57小鼠免疫功能正常,提示BTBR小鼠与ASD有着类似的体内免疫应答反应[37] 。

另外,ASD患儿亦存在体内免疫异常,包括细胞因子的大量产生以及免疫细胞功能异常[38] 。ASD患儿脑内小神经胶质细胞及星形胶质细胞活性增高同时存在脑组织及脑脊液中IFNγ、IL-1β、IL-6、IL-12、TNF-α和巨噬细胞趋化蛋白1水平升高[39] -[41] ,同时,血清中细胞因子IL-1β、IL-6、IL-12p40和MCP-1水平亦增高[42] 。同时,ASD患儿外周血单核细胞数目增高,且在TLR4刺激ASD患儿外周血单核细胞后IL-1β,IL-6和IL-23水平增高,且水平与症状相关[43] -[45] 。而BRBR小鼠有着类似的体内免疫功能异常,研究表明,BTBR小鼠骨髓巨噬细胞产生IL-12 (P40)及IL-10水平增高,经LPS刺激后产生IL-6、IL-12 (P40)及MCP-1水平增高,而IL-10水平降低,提示BTBR小鼠体内免疫主要由M1巨噬细胞参与,同时研究表明该小鼠体内的这种免疫水平与其行为学表现出的自我理毛行为相关[46] 。

脆性X综合征是目前已知的能导致ASD症状的风险基因因素,存在体内ERK信号传导通路的增高,而研究发现BTBR小鼠也存在类似改变[47] 。

5. ASD动物模型的研究现状

目前的ASD动物模型众多,除BTBR这种近交系小鼠是天然的ASD动物模型外,其他ASD动物模型均需要通过一系列手段来构建。其构建方法主要是基于环境因素或遗传学因素。其中,基于环境因素制作的模型主要有:母体免疫模型、丙戊酸模型、丙酸模型以及抗体模型等。而遗传学方面的模型主要有:FMR-1基因模型、MeCP2基因模型、RELN基因模型、15q11-13染色体异常模型、FOX2基因模型等一系列基因敲除小鼠。

然而,虽然ASD模型众多,但当前的ASD模型还存在许多问题。比如,模型成功的评价标准不一。因ASD发病机制复杂,目前所有动物模型只能模拟其部分特征。此外,各种模型造模过程需要一定技术和时间,可重复性较差、操作复杂等,而研究者要考虑表面效度、构建效度和预测效度等多方面因素,才能构建出切实有效的动物模型。BTBR具备以下ASD动物模型的条件:1) 行为异常:社会交往交流障碍、重复刻板行为和狭窄兴趣;2) 脑功能和结构异常:与ASD患儿相似的纹状体和胼胝体的异常;3) 免疫异常:具备与ASD类似的母体免疫异常和体内免疫水平紊乱。且BTBR小鼠是一种天然的ASD小鼠模型,无需造模,可直接应用,且稳定性好。因此,BTBR小鼠是可用于研究ASD的行为异常、脑结构功能异常以及免疫紊乱的理想动物研究模型。然而目前对孤独症的研究表明,一些列与ASD相关基因因素、维生素D水平以及一些神经递质水平的改变尚未在BTBR小鼠中报道,因此,关于这些机制的研究是否能在BTBR小鼠中实现,尚需进一步研究。

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