孤独症谱系障碍实验模型研究进展

doi:10.19586/j.2095-2341.2023.0014

生物技术进展 ›› 2023, Vol. 13 ›› Issue (4): 509-523.DOI: 10.19586/j.2095-2341.2023.0014

• 进展评述 • 上一篇

孤独症谱系障碍实验模型研究进展

方靖靖¹(), 黄昆仑¹^,²^,³(), 仝涛¹^,²^,³()

^1.中国农业大学食品科学与营养工程学院，精准营养与食品质量重点实验室；教育部功能乳品重点实验室，北京 100083
^2.农业农村部农业转基因生物安全评价（食用）重点实验室，北京 100083
^3.食品质量与安全北京实验室，北京 100083

收稿日期:2023-02-13 接受日期:2023-04-17 出版日期:2023-07-25 发布日期:2023-08-03
通讯作者: 黄昆仑,仝涛
作者简介:方靖靖 E-mail: fangjingjing@cau.edu.cn；
基金资助:
北京市自然科学基金项目(7222249);山东省自然科学基金青年基金项目(ZR2021QC118);中国农业大学2115人才工程资助项目

Research Progress on Experimental Models of Autism Spectrum Disorders

Jingjing FANG¹(), Kunlun HUANG¹^,²^,³(), Tao TONG¹^,²^,³()

^1.Key Laboratory of Precision Nutrition and Food Quality； Key Laboratory of Functional Dairy，Ministry of Education，College of Food Science and Nutritional Engineering，China Agricultural University，Beijing 100083，China
^2.Key Laboratory of Safety Assessment of Genetically Modified Organism （Food Safety），the Ministry of Agriculture and Rural Affairs，Beijing 100083，China
^3.Beijing Laboratory for Food Quality and Safety，Beijing 100083，China

Received:2023-02-13 Accepted:2023-04-17 Online:2023-07-25 Published:2023-08-03
Contact: Kunlun HUANG,Tao TONG

摘要/Abstract

摘要：

孤独症谱系障碍（autism spectrum disorder，ASD）是一种典型的由遗传或/和环境因素引起的异质性神经发育障碍。ASD患者的主要特征是社交沟通障碍、语言沟通障碍和刻板行为。目前，ASD的发病机制尚不明确，缺乏有效的治疗方法。综述了近年来用于ASD研究的细胞模型和动物模型，包括PC12细胞、SH-SY5Y细胞、人诱导多能干细胞、淋巴母细胞系和原代神经元，以及非哺乳动物模型、产前丙戊酸暴露模型、BTBR特发性小鼠模型、母体免疫激活模型、基于ASD易感基因构建的啮齿类动物模型和非人灵长类动物模型，总结了现有的ASD细胞模型和动物模型的关键信息，重点阐述了各模型的优势、局限性、构建方法和重要注意事项，以期为探索ASD的发病机制和开发新的诊疗方法奠定基础。

关键词: 孤独症谱系障碍, 细胞模型, 非哺乳动物模型, 啮齿类动物模型, 非人灵长类动物模型

Abstract:

Autism spectrum disorder （ASD） is a typical heterogeneous neurodevelopmental disorder induced by genetic or/and environmental factors. The main characteristics of ASD patients are social communication deficits， verbal communication disorders， and stereotyped behaviors. Currently， the pathogenesis of ASD is not clear， and there is a lack of effective treatment methods. This review focused on cell models and animal models used for ASD research in recent years， including PC12 cells， SH-SY5Y cells， human induced pluripotent stem cells， lymphoblastoid cell lines， and primary neurons， as well as non-mammalian models， prenatal valproic acid exposure models， BTBR idiopathic mouse models， maternal immune activation models， rodent models based on ASD susceptibility genes， and non-human primate models. We consolidated the key information on the available cell models and animal models of ASD and highlighted the advantages， limitations， construction methods， and important caveats of each model， which was expected to lay a foundation for exploring the pathogenesis and developing new diagnosis and treatment methods for ASD.

Key words: autism spectrum disorder, cell models, non-mammalian models, rodent models, non-human primate models

中图分类号:

R749

方靖靖, 黄昆仑, 仝涛. 孤独症谱系障碍实验模型研究进展[J]. 生物技术进展, 2023, 13(4): 509-523.

Jingjing FANG, Kunlun HUANG, Tao TONG. Research Progress on Experimental Models of Autism Spectrum Disorders[J]. Current Biotechnology, 2023, 13(4): 509-523.

图/表 5

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细胞模型	潜在应用	优点	缺点
PC12细胞模型	探索ASD易感基因如NLGN-3和PTEN的功能^[4]及VPA等环境因素诱发ASD的分子机制^[5]	研究神经发育的标准细胞模型	是一类肿瘤细胞，经过多次传代后其形态和特性都会发生变化
SH-SY5Y细胞模型	探索ASD易感基因如SHANK2的功能^[6]；研究ASD的分子机制，如Caspase-3凋亡级联、甲基化等^[7-8]	研究神经表型和神经变性疾病的良好细胞模型	不能观察神经发育过程；未分化细胞对神经毒素和神经保护剂的敏感性较低
hiPSCs细胞模型	探讨ASD易感基因如DSCAM的功能^[10]；研究ASD的基因-环境交互作用；探索ASD的潜在治疗方法，如胰岛素生长因子1^[11]；ASD相关脑类器官的开发^[13]	具有胚胎干细胞的形态和遗传特征；发展个体化医学	无法观察到典型的病理表型；必须严格控制致瘤风险
LCLs细胞模型	探索ASD与氧化应激的关系；研究线粒体功能障碍与ASD的关系；筛选防治ASD的候选药物^[14-15]	反映机体的免疫状态；协助疾病诊断	采集后难以保存，不能传代培养；患者的LCLs标本往往需要反复采集
原代神经元细胞模型	探索Wnt信号通路、内质网应激、NLGN表达与ASD的关系^[16-17]	更接近神经元在人体内的状态	无法完全模拟体内环境

细胞模型	潜在应用	优点	缺点
PC12细胞模型	探索ASD易感基因如NLGN-3和PTEN的功能^[4]及VPA等环境因素诱发ASD的分子机制^[5]	研究神经发育的标准细胞模型	是一类肿瘤细胞，经过多次传代后其形态和特性都会发生变化
SH-SY5Y细胞模型	探索ASD易感基因如SHANK2的功能^[6]；研究ASD的分子机制，如Caspase-3凋亡级联、甲基化等^[7-8]	研究神经表型和神经变性疾病的良好细胞模型	不能观察神经发育过程；未分化细胞对神经毒素和神经保护剂的敏感性较低
hiPSCs细胞模型	探讨ASD易感基因如DSCAM的功能^[10]；研究ASD的基因-环境交互作用；探索ASD的潜在治疗方法，如胰岛素生长因子1^[11]；ASD相关脑类器官的开发^[13]	具有胚胎干细胞的形态和遗传特征；发展个体化医学	无法观察到典型的病理表型；必须严格控制致瘤风险
LCLs细胞模型	探索ASD与氧化应激的关系；研究线粒体功能障碍与ASD的关系；筛选防治ASD的候选药物^[14-15]	反映机体的免疫状态；协助疾病诊断	采集后难以保存，不能传代培养；患者的LCLs标本往往需要反复采集
原代神经元细胞模型	探索Wnt信号通路、内质网应激、NLGN表达与ASD的关系^[16-17]	更接近神经元在人体内的状态	无法完全模拟体内环境

非哺乳动物模型	表型特征	潜在应用	优点	缺点
果蝇模型	FMR1突变果蝇之间的互动较少，存在学习记忆缺陷^[18]；双酚A诱导的果蝇表现出增加的重复行为和异常的社会互动^[19]	阐明ASD的分子机制；筛查ASD风险基因和药物	生殖周期短、低成本，简单保守的基因组	生理、解剖和行为特征都与人类有较大差异
秀丽隐杆线虫模型	NLGN-1基因R433C错义突变可导致社会功能障碍^[22]	探索新的ASD易感基因及ASD的潜在治疗方法	保守且简单的神经元通路	大脑结构和生理特征与人类有较大差异
斑马鱼模型	VPA处理可降低斑马鱼的细胞增殖和颜色偏好^[24]；下调SHANK3同源基因可降低斑马鱼的头围和对触摸的反应能力^[25]	探讨ASD易感基因的功能；筛选ASD候选药物	繁殖快、药物使用方便且成本低；表现出明确定义的刻板样行为	低同源性；在解剖和行为特征上与人类存在巨大差异
鸣禽类动物模型	研究CNTNAP2等语言相关基因在鸣禽学习发声回路中的作用^[26]	揭示ASD语言障碍的相关分子机制	模拟语言沟通障碍	大脑不发达

非哺乳动物模型	表型特征	潜在应用	优点	缺点
果蝇模型	FMR1突变果蝇之间的互动较少，存在学习记忆缺陷^[18]；双酚A诱导的果蝇表现出增加的重复行为和异常的社会互动^[19]	阐明ASD的分子机制；筛查ASD风险基因和药物	生殖周期短、低成本，简单保守的基因组	生理、解剖和行为特征都与人类有较大差异
秀丽隐杆线虫模型	NLGN-1基因R433C错义突变可导致社会功能障碍^[22]	探索新的ASD易感基因及ASD的潜在治疗方法	保守且简单的神经元通路	大脑结构和生理特征与人类有较大差异
斑马鱼模型	VPA处理可降低斑马鱼的细胞增殖和颜色偏好^[24]；下调SHANK3同源基因可降低斑马鱼的头围和对触摸的反应能力^[25]	探讨ASD易感基因的功能；筛选ASD候选药物	繁殖快、药物使用方便且成本低；表现出明确定义的刻板样行为	低同源性；在解剖和行为特征上与人类存在巨大差异
鸣禽类动物模型	研究CNTNAP2等语言相关基因在鸣禽学习发声回路中的作用^[26]	揭示ASD语言障碍的相关分子机制	模拟语言沟通障碍	大脑不发达

啮齿类动物模型	表型特征	潜在应用	优点	缺点
产前丙戊酸暴露模型	社交能力受损；超声发声频率降低，持续时间缩短；呈现出理毛和挖掘等重复性行为增加的总体趋势；表现出与ASD患者相似的肠道菌群失调^[31]	探究VPA诱导ASD分子机制；筛选候选药物，如白藜芦醇^[30]	可以模拟典型和核心ASD表型	目前尚无统一、标准化的模型构建方法
BTBR特发性小鼠模型	表现出明显的学习和认知障碍、社交障碍、发声能力异常；表现出增加的重复行为^[34]	探索ASD的病理；筛选候选药物	表型和解剖学特征与ASD患者一致	BTBR小鼠的异常行为主要由Kmo基因的3个单核苷酸多态性引起
MIA模型	表现为超声发声频率降低，社会偏好减少，刻板行为增多；胃肠道屏障缺陷，肠道微生物群紊乱	筛选ASD的潜在治疗方法，如脆弱拟杆菌^[37]	显示ASD的核心症状和常见的神经病理学改变	Poly I：C诱导MIA模型的方法不统一，注射剂量、注射时间、注射次数不一

孤独症谱系障碍实验模型研究进展

Research Progress on Experimental Models of Autism Spectrum Disorders

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ASD易感基因	表型特征	潜在应用	优点	缺点
NLGN家族	NLGN-1基因敲除小鼠表现出空间学习记忆缺陷，刻板行为增多^[40]；NLGN-2基因敲除小鼠表现出探索活动减少、超声发声减少等行为异常^[41]；NLGN-3 R451C基因敲入小鼠的社交能力受损，空间学习能力增强^[42]；NLGN-4基因敲除小鼠表现出社会交往和沟通障碍^[43]	探索NLGN家族在ASD发病中的作用	靶基因以及NLGN家族的基因功能已经明确	局限于针对NLGN基因缺陷的ASD患者的研究；不同的突变模型表现出不同的表型特征
NRXN家族	NRXN-1α和NRXN-2α基因敲除小鼠表现出社交障碍和焦虑相关行为缺陷^[44]；NRXN-4即CNTNAP2基因敲除的大鼠和小鼠表现出增加的重复行为和社会行为障碍^[46]	探讨NRXN家族在ASD中的作用；利培酮等候选药物的筛选^[46]	靶基因以及NRXN家族的基因功能已经明确	研究针对NRXN基因缺陷的ASD患者；不同的突变模式表现出不同的表型
SHANK家族	SHANK3α基因敲除小鼠对探索新事物的兴趣降低；SHANK3 PDZ敲除小鼠表现出增加的重复行为和社会互动障碍^[48]	探索SAHNK家族在ASD中的作用	SHANK家族的靶基因和功能已经明确；SHANK3是与ASD最相关的基因之一	仅限于具有SHANK缺陷的ASD；不同的突变模式表现出不同的表型
MECP2	MECP2突变小鼠表现出社会行为下降，学习记忆能力异常，重复行为增加^[49-50]	探索MECP2在ASD发生中的作用	靶基因和MECP2的功能已经明确	仅限于伴随MECP2基因缺陷的ASD
FMR1	FMR1基因敲除小鼠表现出增加的重复行为、焦虑和社交障碍^[51]；FMR1基因突变小鼠表现出增加的重复行为和社会行为障碍^[52]	探讨FMR1在ASD中的作用	建立关键疾病模型，探索ASD的病理生理学特征和分子机制	仅限于伴有FMR1缺陷和FXS的ASD；未能完全呈现FXS和ASD表型
TSC1/2	浦肯野细胞中TSC1和TSC2的缺失会导致小鼠的社交障碍、发声异常和重复行为增加^[53]；小鼠丘脑中TSC1缺失导致成年小鼠理毛行为和癫痫发作增加^[54]	ASD的病理学研究；开发ASD潜在治疗方法，如mTOR抑制剂^[54]	靶基因和TSC1/2的功能已经明确	局限于伴有TSC1/2基因缺陷的ASD
PTEN	小脑浦肯野细胞中PTEN的缺失导致社交能力受损、重复行为增多^[55]	了解PTEN在ASD中的作用；提示mTOR抑制剂作为治疗药物的潜力^[56]	PTEN的功能已经明确；在多达20%的ASD儿童中发现了PTEN突变	局限于伴有PTEN基因缺陷的ASD
UBE3A	前额叶皮质中UBE3A的过表达使小鼠表现出重复性行为增加和社会交往缺陷	介绍ASD病因学的新展望；筛选治疗ASD候选药物，如维A酸^[57]	靶基因和UBE3A的功能已经明确	局限于存在UBE3A缺陷的ASD；一些突变模型没有表现出ASD样行为特征

非人灵长类动物模型	表型特征	潜在应用	优点	缺点
SHANK3突变食蟹猴	重复行为增加，社交和学习缺陷	对ASD神经机制具有重要的研究价值；开发潜在干预措施	与人类同源性最高；通过面部表情、肢体和声音进行社会交流；模拟ASD患者的行为缺陷；拥有参与社会行为的关键脑区；社会注意力缺陷可以通过眼动追踪技术进行评估	生命周期和研究周期长；维护费用昂贵；需要专门的设施；动物伦理制度严格
MECP2突变食蟹猴	焦虑增加、重复活动和社交缺陷
VPA暴露狨猴	缺乏社交动机和兴趣下降
Poly I:C恒河猴	重复行为增加和社会能力受损
X射线照射恒河猴	更多的刻板行为和认知行为障碍
母体抗体暴露恒河猴	一定的社交障碍和脑容量增加

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