孤独症谱系障碍小鼠模型行为学检测方法

doi:10.16288/j.yczz.20-391

遗传 ›› 2021, Vol. 43 ›› Issue (5): 501-519.doi: 10.16288/j.yczz.20-391

孤独症谱系障碍小鼠模型行为学检测方法

王剑飞, 韩俊海, 张子超()

东南大学生命科学与技术学院,发育与疾病相关基因教育部重点实验室,南京 210096

收稿日期:2020-11-18 修回日期:2021-02-08 出版日期:2021-05-20 发布日期:2021-03-19
作者简介:王剑飞,在读硕士研究生,专业方向：孤独症致病机制。E-mail: w13912971049@163.com
基金资助:
国家自然科学基金项目(编号)(31871374);国家自然科学基金项目(编号)(81730034);江苏省自然科学基金项目(编号)资助(BK20170080)

Behavioral analyses in mouse models of autism spectrum disorders

Jianfei Wang, Junhai Han, Zichao Zhang()

The Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing 210096, China

Received:2020-11-18 Revised:2021-02-08 Online:2021-05-20 Published:2021-03-19
Supported by:
Supported by the National Natural Science Foundation of China Nos(31871374);Supported by the National Natural Science Foundation of China Nos(81730034);the Natural Science Foundation of Jiangsu Province No(BK20170080)

摘要/Abstract

摘要：

孤独症谱系障碍(autism spectrum disorder, ASD)是一种遗传相关的神经系统发育性疾病,患者主要呈现社交缺陷、沟通障碍、重复刻板行为和学习记忆障碍等核心症状。小鼠模型是探究孤独症谱系障碍的致病机理和寻找潜在治疗方法的重要工具,而小鼠行为学的观测和分析可以帮助人们更好地了解不同遗传操作对相应孤独症表型的影响,从而阐释疾病机理。本文列举了针对孤独症患者核心缺陷的相关小鼠行为学分析方法,包括检测社交缺陷的三厢社交实验、居住者-入侵者实验、筑巢实验和超声波检测;检测重复刻板行为的Y迷宫自主选择实验、捋毛实验、刻板行为分析实验和弹珠埋藏实验;检测焦虑行为的旷场实验、高架十字迷宫实验和明暗穿梭实验;检测学习和记忆障碍的新事物选择实验和水迷宫实验。本文详细描述了这些行为学实验的标准操作流程、注意事项以及规范的数据分析方法,可以帮助研究人员进行相关实验设计。同时本文对已知孤独症小鼠遗传模型中的各项行为学表型进行了汇总和比较,为相关研究人员提供系统参照。

关键词: 孤独症谱系障碍, 小鼠行为学分析, 社交障碍, 重复刻板, 学习记忆, 焦虑

Abstract:

Autism spectrum disorder is a group of genetically-related developmental disorders of the nervous system. Patients mainly present with core symptoms such as social behavior defects, repetitive stereotyped behaviors, and learning and memory disorders. The mouse models are critical for the studies of the pathogenic mechanisms and potential therapeutic strategies of autism spectrum disorder. The assessments of mouse behaviors provide understandings of the effects of different genetic manipulations as well as pathogenic mechanisms of these diseases. This article describes various mouse behavioral assays corresponding to the core symptoms of ASD patients and provides a detailed description of protocols, cautions, and data analysis for those assays, thereby helping researchers to establish their own experimental designs. In addition, behavioral phenotypes of currently known ASD mouse models are summarized to provide a reference for researchers in the field.

Key words: autism spectrum disorder, mouse behavioral analysis, social disorder, repetitive behavior, learning and memory, anxiety

王剑飞, 韩俊海, 张子超. 孤独症谱系障碍小鼠模型行为学检测方法[J]. 遗传, 2021, 43(5): 501-519.

Jianfei Wang, Junhai Han, Zichao Zhang. Behavioral analyses in mouse models of autism spectrum disorders[J]. Hereditas(Beijing), 2021, 43(5): 501-519.

图/表 13

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表1

ASD小鼠模型社交行为检测"

小鼠模型	基因ID	三厢社交实验	居住者-入侵者实验	筑巢实验	母子分离/求偶实验	参考文献
Mecp2^-/y	17257	T_E >T_S, T_S2< T_S1		S=0.5WT	N_U、T_U↑, C_u↓	[58,59]
Shank1	243961	T_E<T_S	N_S=WT		N_U1↓	[60]
Shank2^-/-	210274	T_E>T_S, T_S2>T_S1		S=0.5WT	N_U、N_U1↓	[12,61]
Shank3^e4-9	58234	T_E>T_S, T_S2<T_S1			N_U1↓	[62]
Shank3^e13	58234	T_E<T_S, T_S2<T_S1	N_S=WT			[63,64]
Shank3B^-/-	58234	T_E>T_S, T_S2≈T_S1	N_S=0.5WT			[65]
Fmr1^-/y	14265	T_E>T_S, T_S2<T_S1	N_A=4WT, N_S=2WT		N_U、T_U、N_U1、T_U1↓	[66~68]
Trim32^-/-	69807	T_E<T_S, T_S2≈T_S1	N_S=0.5WT	S=0.6WT		[35]
Gabrb3^+/-	14402	T_E>T_S, T_S2<T_S1		S=0.6WT		[59,69]
Arid1b^+/-	239985	T_E≈T_S, T_S2<T_S1	N_S=0.6WT		T_U↑	[48,70]
Pax2^+/-	18504	T_E<T_S				[71]
Syngap^+/-	240057	T_E≈T_S, T_S2≈T_S1	N_S=0.9WT			[72]
Cntnap2^-/-	66797	T_E≈T_S		S=0.3WT	N_U、N_U1↓	[12,73]
Chd8^+/-	67772	T_E<T_S, T_S2>T_S1	N_S=WT	S=WT		[74,75]
Cttnbp2^-/-	30785	T_E≈T_S, T_S2≈T_S1	N_S=0.5WT		N_U、T_U↓	[76]
Dlg2^-/-	23859	T_E≈T_S, T_S2>T_S1	N_S=0.5WT			[77]
Nexmif ^-/-	2455555	T_E≈T_S, T_S2≈ T_S1				[78]
Nrxn1α^-/-	18189	T_E<T_S, T_S2>T_S1	N_A=3WT		N_U、T_U↓, C_u↓	[79,80]
Nlgn3^R451C	245537	T_E<T_S, T_S2>T_S1	N_A=2WT		N_U、N_U1↓	[81,82]
Nlgn4^-/-	100113365	T_E>T_S, T_S2<T_S1	N_A=0.5WT	S=0.7WT	N_U1↓	[83]
Nlgn1^-/-	192167	T_E<T_S, T_S2<T_S1	N_S=0.7WT	S=0.6WT	N_U↑	[84,85]
Pten^+/-	19211	T_E≈T_S, T_S2≈T_S1	N_A>10WT		N_U、T_U↓	[86,87]
Pten^-/-	19211	T_E≈T_S	N_S=0.5WT			[86]
Tsc1^-/- Tsc1^+/-	64930	T_E≈T_S, T_S2≈T_S1				[88]
Tsc2^+/-	22084	T_E≈T_S, T_S2≈T_S1				[89]
CBP^ΔCH1/ΔCH1	94212	T_E≈T_S	N_A=2WT	S=0.5WT		[90]
En2^-/-	13799		N_S=0.3WT			[91]
4E-BP2^-/-	13688	T_E>T_S			N_U、T_U↑, C_u、N_U1↓	[12,44]
Oxt^-/-	18429	T_E<T_S, T_S2>T_S			N_U、T_U↓	[92]
Foxp2	114142		N_S=0.6WT		N_U↓	[93,94]
15q11-13		T_E≈T_S, T_S2≈T_S1			N_U↑, N_U1↓	[95]
17p11.2		T_E<T_S, T_S2>T_S	N_A=6WT	S=0.5WT	N_U、T_U↓	[96,97]
VPA		T_E≈T_S	N_S=0.6WT			[98]
BTBR		T_E>T_S, T_S2<T_S1	N_S=0.4WT		N_U、T_U↑, C_u、N_U1↓	[99]
BALB		T_E>T_S, T_S2>T_S1	N_S↓			[100]
C58/J		T_E>T_S, T_S2>T_S1			T_U↓	[101]

表1

表2

表3

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孤独症谱系障碍小鼠模型行为学检测方法

Behavioral analyses in mouse models of autism spectrum disorders

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小鼠模型	基因ID	捋毛实验	Y-迷宫自主选择实验	刻板行为分析实验	弹珠埋藏实验	参考文献
Shank1	243961	T_G=WT				[60]
Shank2^-/-	210274	T_G=2.5WT		N_c↑		[12,61]
Shank3^e4-9	58234	T_G=8WT			N_b=0.5WT	[62]
Shank3^e13	58234	T_G=2.5WT			N_b=WT	[63,64]
Shank3B^-/-	58234	T_G=2WT			N_b=0.4WT	[65]
Fmr1^-/y	14265	T_G=2WT		N_c↑		[66~68]
Trim32^-/-	69807	T_G=3WT	R=1.3WT			[35]
Gabrb3^+/-	14402			N_c↑		[59,69]
Arid1b^+/-	239985	T_G=6WT			N_b=WT	[48,70]
Pax2^+/-	18504	T_G=3WT	R≈WT			[71]
Syngap^+/-	240057		R=2WT	N_c↑		[72]
Cntnap2^+/-	66797	T_G=4WT	R=3WT			[12,73]
Chd8^+/-	67772	T_G=WT			N_b=WT	[74,75]
Cttnbp2^-/-	30785	T_G=WT		无差异	N_b=2WT	[76]
Dlg2^-/-	23859	T_G=2WT				[77]
Nexmif ^-/-	2455555	T_G=2.5WT				[78]
Nrxn1α^-/-	18189	T_G=2WT		N_c↑	N_b=WT	[79,80]
Nlgn3^R451C	245537	T_G=WT		N_c↑		[81,82]
Nlgn4^-/-	100113365	T_G=WT				[83]
Nlgn1^-/-	192167	T_G=2WT		无差异	N_b=WT	[84,85]
Pten^+/-	19211				N_b=1.5WT	[86,87]
Pten^-/-	19211	T_G=0.5WT				[86]
Tsc1^-/- Tsc1^+/-	64930	T_G=2.5WT	R=2WT			[88]
Tsc2^+/-	22084				N_b=1.25WT	[89]
CBP^ΔCH1/ΔCH1	94212	T_G=8WT		N_c↑		[90]
En2^-/-	13799	T_G=3WT				[91]
4E-BP2^-/-	13688	T_G=2WT			N_b=2WT	[12,44]
BTBR		T_G=4WT			N_b=2WT	[99]
C58/J		T_G=3WT		N_c↑	N_b=0.4WT	[101]

小鼠模型	基因ID	旷场实验	高架十字迷宫实验	明暗穿梭实验	新事物识别实验	水迷宫实验	参考文献
Mecp2^-/y	17257	R_t=0.5WT	R_to=0.5WT		T_N>T_F		[58,59]
Shank1	243961	R_t=0.6WT	R_to=WT	N_l=0.5WT	T_N>T_F	T_L=WT, N_T=WT	[60]
Shank2^-/-	210274		R_to=0.5WT		T_N>T_F	T_L=1.5WT, N_T=0.5WT	[12,61]
Shank3^e4-9	58234	V=0.5WT		T_l=WT		T_L>1.5WT, N_T<WT	[62]
Shank3^e13	58234	R_t=0.7WT	R_to=0.5WT	T_l=WT		T_L=WT, N_T=WT	[63,64]
Shank3B^-/-	58234		R_to=0.5WT			T_L=1.6WT, N_T=0.25WT	[65]
Arid1b^+/-	239985	V=0.25WT	R_to=0.25WT	T_l=0.6WT	T_N=T_F	T_L=3WT, N_T=0.4WT	[48,70]
Pax2^+/-	18504		R_to=WT				[71]
Syngap^+/-	240057	R_t=1.3WT	R_to=1.5WT	T_l=WT			[72]
Cntnap2^-/-	66797	V=1.5WT		T_l=WT		T_L=WT, N_T=WT	[12,73]
Chd8^+/-	67772	R_t=0.5WT	R_to=0.3WT	T_l= 0.66WT			[74,75]
Cttnbp2^-/-	30785	R_t=1.2WT	R_to=1.3WT		T_N=T_F		[76]
Dlg2^-/-	23859	R_t=0.5WT	R_to=WT	T_l=0.5WT			[77]
Nexmif ^-/-	2455555	R_t=2WT					[78]
Nrxn1α^-/-	18189	R_t=WT	R_to=WT			T_L=WT, N_T=WT	[79,80]
Nlgn3^R451C	245537	R_t=WT	R_to=WT	T_l=WT			[81,82]
Nlgn4^-/-	100113365	R_t=WT	R_to=WT			T_L=WT, N_T=WT	[83]
Nlgn1^-/-	192167	R_t=WT	R_to=WT	T_l=WT	T_N>T_F	T_L=WT, N_T=0.3WT	[84,85]
Pten^-/-	19211	R_t=0.5WT				T_L=WT, N_T=WT	[88]
Tsc2^+/-	22084	R_t=0.5WT				T_L=1.5WT, N_T=0.5WT	[89]
CBP^ΔCH1/ΔCH1	94212	R_t=WT	R_to=WT		T_N=T_F		[90]
En2^-/-	13799				T_N<T_F	T_L=2WT, N_T=0.7WT	[91]
4E-BP2^-/-	13688	R_t=WT	R_to=WT	N_l=0.5WT			[12,44]
Foxp2		R_t=WT	R_to=WT				[95]
15q11-13						T_L=WT, N_T=WT	[96,97]
17p11.2		R_t=0.7WT	R_to=0.5WT				[98]
VPA		R_t=0.2WT	R_to=0.5WT			T_L=3WT, N_T=0.3WT	[99]
BTBR		R_t=0.5WT	R_to=0.7WT	T_l=WT	T_N<T_F	T_L=WT, N_T=0.8WT	[100]
C58/J		R_t=0.5WT	R_to=0.5WT		T_N<T_F		[101]