精神分裂症动物模型的研究概述

doi:10.12300/j.issn.1674-5817.2022.174

实验动物与比较医学 ›› 2023, Vol. 43 ›› Issue (2): 145-155.DOI: 10.12300/j.issn.1674-5817.2022.174

精神分裂症动物模型的研究概述

胡玲¹, 胡志斌¹^,², 胡筠卿¹^,², 丁玉强¹^,²()()

^1.复旦大学实验动物科学部, 上海 200032
^2.复旦大学脑科学研究院, 上海 200032

收稿日期:2022-11-10 修回日期:2023-02-13 出版日期:2023-04-25 发布日期:2023-05-16
通讯作者: 丁玉强（1966—），男，教授，博士生导师，研究方向：疾病动物模型与神经系统疾病发生机制。E-mail：dingyuqiang@vip.163.com。ORCID： 0000-0003-1202-4635
作者简介:胡玲（1989—），女，博士，副研究员，研究方向：疾病动物模型与神经系统疾病发生机制。E-mail：06huling@163.com；
胡志斌（1997—），男，博士研究生，研究方向：疾病动物模型与神经系统疾病发生机制。E-mail： zbhu20@fudan.edu.cn
基金资助:
国家自然科学基金面上项目“Ulk4基因在精神分裂症发病作用和机制-小鼠模型研究”(32271072)

Overview of Studies in Animal Models of Schizophrenia

Ling HU¹, Zhibin HU¹^,², Yunqing HU¹^,², Yuqiang DING¹^,²()()

^1.Department of Laboratory Animal Science, Fudan University, Shanghai 200032, China
^2.Institutes of Brain Science, Fudan University, Shanghai 200032, China

Received:2022-11-10 Revised:2023-02-13 Published:2023-04-25 Online:2023-05-16
Contact: DING Yuqiang (ORCID: 0000-0003-1202-4635), E-mail: dingyuqiang@vip.163.com

摘要/Abstract

摘要：

精神分裂症（schizophrenia）是一类极具破坏性的复杂精神疾病，伴有各种阳性和阴性症状以及认知障碍，给社会带来沉重负担。在神经发育过程中遗传因素和环境因素之间具有复杂的相互作用，使得精神分裂症病因的阐明和治疗的发展面临很大挑战。因此，制备合适的动物模型可帮助人们理解各种致病因素引起精神分裂症的神经生物学基础，为寻找新的治疗方法提供线索和理论依据。本文介绍了几种主要的精神分裂症动物模型的造模方式，包括神经发育模型、药物诱导模型和遗传模型；同时对精神分裂症动物的行为学评估、组织学分析以及可能的分子机制进行了概括，以期为精神分裂症动物模型的应用和改进提供参考。

关键词: 精神分裂症, 动物模型, 行为学分析, 多巴胺, γ-氨基丁酸

Abstract:

Schizophrenia (SCZ) is a highly destructive and complex psychiatric disorder illness, accompanied by a variety of positive and negative symptoms along with cognitive impairment, which brings a heavy social burden. Elucidation of the pathogenesis and therapeutic development is challenging because the complex interplay between genetic risk factors and environmental factors in essential neurodevelopmental processes. Therefore, preparing appropriate animal models can help people better understanding the neurobiological basis of SCZ and provide theoretical basis for finding new treatments. In order to provide reference for the application and improvement of SCZ animal models, this commentary reviewed several main modeling methods for animal models of SCZ, including neurodevelopmental models, drug-induced animal models, and genetic models, and the behavioral evaluation, histological analysis and possible molecular mechanisms of SCZ animal models were also outlined.

Key words: Schizophrenia, Animal models, Behavior analysis, Dopamine, γ-aminobutyric acid

中图分类号:

R-332

胡玲, 胡志斌, 胡筠卿, 丁玉强. 精神分裂症动物模型的研究概述[J]. 实验动物与比较医学, 2023, 43(2): 145-155.

Ling HU, Zhibin HU, Yunqing HU, Yuqiang DING. Overview of Studies in Animal Models of Schizophrenia[J]. Laboratory Animal and Comparative Medicine, 2023, 43(2): 145-155.

图/表 1

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模型类型 Type of model	操作方式 Operation	行为学表型 Behavioral phenotype	组织学表型 Histological phenotype	参考文献 Reference
神经发育学模型 Neurodevelopmental model	出生前注射甲基氧化偶氮甲醇	对多巴胺通路激动剂安非他明的运动反应增加，社交活动减少，感觉运动门控缺陷，记忆障碍，焦虑增加	内侧前额叶体积减少，侧脑室和第三脑室体积增加，边缘和皮层区域的中间神经元标志物减少，腹侧被盖区多巴胺神经元活性增加	[10]
	出生后社会隔离	自发运动增加，对新奇事物的反应增强，感觉运动门控障碍，认知障碍，焦虑和攻击性增加	前额叶体积减少，树突棘密度降低，海马中PV阳性的中间神经元降低	[11-13]
	母体免疫激活	感觉运动门控异常、社交行为异常、焦虑样和抑郁样行为增加等阴性症状，同时出现对多巴胺通路激动剂安非他明的运动反应增加等阳性症状	树突棘的密度下降，树突的复杂性下降，抑制性神经元的数量也减少。磁共振成像研究发现母体免疫激活的后代脑室扩大和脑区体积减少	[15-16,18]
	胚胎期和青春期进行刺激	根据胚胎期和青春期的刺激确定	根据胚胎期和青春期的刺激确定	[15,19]
药物诱导模型 Drug-induced model	多巴胺通路激动剂安非他命	运动过度，空间工作记忆障碍，感觉运动门控缺陷，潜在抑制缺陷	NMDA受体表达异常，树突形态改变，伏隔核和纹状体中多巴胺的释放增加	[24-26]
	氯胺酮	损害空间工作记忆，引起焦虑样行为、社会行为改变，运动过度，感觉运动门控障碍	多个脑区BDNF蛋白的表达水平降低，炎性细胞因子失衡，海马区域PV阳性神经元的数量下降	[37-41]
	苯环己哌啶	记忆和学习障碍，社交能力受损，活动升高，感觉运动门控异常	前额叶皮层多巴胺、谷氨酸、5羟色胺以及去甲肾上腺素释放增加，γ-氨基丁酸释放降低，BDNF/TrkB的水平下调	[30-34]
	MK-801	运动过度，感觉运动门控缺陷，社交能力下降，条件性恐惧记忆异常	运动过度，感觉运动门控缺陷，社交能力下降，条件性恐惧记忆的异常	[42-45]
遗传模型 Genetic model	DISC1	识别记忆、社交和焦虑行为缺陷，感觉运动门控异常等	脑室增大，皮质厚度和脑容量减少，皮层中γ-氨基丁酸能神经元密度降低，NMDA受体亚基和PSD-95的表达减少	[50-54]
	22q11.2缺失综合征	感觉运动门控异常，恐惧条件反射异常，空间记忆受损等	皮层和皮层下灰质体积改变，脑室增大，树突棘密度和树突复杂性减少，多巴胺和γ-氨基丁酸系统紊乱	[56-58]
	NRG1	活动和探索行为增加，在自发交替测试中工作记忆异常，感觉运动门控异常	脑中功能性的NMDA受体水平降低，海马锥体神经元上的树突棘密度减少	[61-62]
	Dysbindin	多动，学习和记忆缺陷，冲动和强迫行为增加	多巴胺释放增加，细胞表面D2受体过表达	[66-67]
	Ulk4	感觉运动门控异常，工作和空间记忆异常	Akt-Gsk3β信号通路异常，Gsk3β活性增加	[71]

模型类型 Type of model	操作方式 Operation	行为学表型 Behavioral phenotype	组织学表型 Histological phenotype	参考文献 Reference
神经发育学模型 Neurodevelopmental model	出生前注射甲基氧化偶氮甲醇	对多巴胺通路激动剂安非他明的运动反应增加，社交活动减少，感觉运动门控缺陷，记忆障碍，焦虑增加	内侧前额叶体积减少，侧脑室和第三脑室体积增加，边缘和皮层区域的中间神经元标志物减少，腹侧被盖区多巴胺神经元活性增加	[10]
	出生后社会隔离	自发运动增加，对新奇事物的反应增强，感觉运动门控障碍，认知障碍，焦虑和攻击性增加	前额叶体积减少，树突棘密度降低，海马中PV阳性的中间神经元降低	[11-13]
	母体免疫激活	感觉运动门控异常、社交行为异常、焦虑样和抑郁样行为增加等阴性症状，同时出现对多巴胺通路激动剂安非他明的运动反应增加等阳性症状	树突棘的密度下降，树突的复杂性下降，抑制性神经元的数量也减少。磁共振成像研究发现母体免疫激活的后代脑室扩大和脑区体积减少	[15-16,18]
	胚胎期和青春期进行刺激	根据胚胎期和青春期的刺激确定	根据胚胎期和青春期的刺激确定	[15,19]
药物诱导模型 Drug-induced model	多巴胺通路激动剂安非他命	运动过度，空间工作记忆障碍，感觉运动门控缺陷，潜在抑制缺陷	NMDA受体表达异常，树突形态改变，伏隔核和纹状体中多巴胺的释放增加	[24-26]
	氯胺酮	损害空间工作记忆，引起焦虑样行为、社会行为改变，运动过度，感觉运动门控障碍	多个脑区BDNF蛋白的表达水平降低，炎性细胞因子失衡，海马区域PV阳性神经元的数量下降	[37-41]
	苯环己哌啶	记忆和学习障碍，社交能力受损，活动升高，感觉运动门控异常	前额叶皮层多巴胺、谷氨酸、5羟色胺以及去甲肾上腺素释放增加，γ-氨基丁酸释放降低，BDNF/TrkB的水平下调	[30-34]
	MK-801	运动过度，感觉运动门控缺陷，社交能力下降，条件性恐惧记忆异常	运动过度，感觉运动门控缺陷，社交能力下降，条件性恐惧记忆的异常	[42-45]
遗传模型 Genetic model	DISC1	识别记忆、社交和焦虑行为缺陷，感觉运动门控异常等	脑室增大，皮质厚度和脑容量减少，皮层中γ-氨基丁酸能神经元密度降低，NMDA受体亚基和PSD-95的表达减少	[50-54]
	22q11.2缺失综合征	感觉运动门控异常，恐惧条件反射异常，空间记忆受损等	皮层和皮层下灰质体积改变，脑室增大，树突棘密度和树突复杂性减少，多巴胺和γ-氨基丁酸系统紊乱	[56-58]
	NRG1	活动和探索行为增加，在自发交替测试中工作记忆异常，感觉运动门控异常	脑中功能性的NMDA受体水平降低，海马锥体神经元上的树突棘密度减少	[61-62]
	Dysbindin	多动，学习和记忆缺陷，冲动和强迫行为增加	多巴胺释放增加，细胞表面D2受体过表达	[66-67]
	Ulk4	感觉运动门控异常，工作和空间记忆异常	Akt-Gsk3β信号通路异常，Gsk3β活性增加	[71]

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精神分裂症动物模型的研究概述

Overview of Studies in Animal Models of Schizophrenia

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