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Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans.显性负性 DISC1 转基因小鼠表现出可通过适用于人类的检测方法检测到的精神分裂症相关表型。
Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. doi: 10.1073/pnas.0704774104. Epub 2007 Aug 3.
2
Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia.在小鼠中突变型人类DISC1的诱导表达与类似精神分裂症的大脑和行为异常有关。
Mol Psychiatry. 2008 Feb;13(2):173-86, 115. doi: 10.1038/sj.mp.4002079. Epub 2007 Sep 11.
3
Dominant negative DISC1 mutant mice display specific social behaviour deficits and aberration in BDNF and cannabinoid receptor expression.显性负性 DISC1 突变小鼠表现出特定的社会行为缺陷和 BDNF 及大麻素受体表达异常。
World J Biol Psychiatry. 2014 Jan;15(1):76-82. doi: 10.3109/15622975.2013.841993. Epub 2013 Nov 13.
4
Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1.表达截短型Disc1的转基因小鼠中与精神分裂症相关的神经和行为表型。
J Neurosci. 2008 Oct 22;28(43):10893-904. doi: 10.1523/JNEUROSCI.3299-08.2008.
5
Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders.突变型人 DISC1 基因在产前和产后的表达对转基因小鼠神经行为表型的差异影响：精神疾病神经发育起源的证据。
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6
Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood.新生儿免疫激活与突变型DISC1对成年期表型变化的联合作用。
Behav Brain Res. 2010 Jan 5;206(1):32-7. doi: 10.1016/j.bbr.2009.08.027. Epub 2009 Aug 28.
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Comprehensive behavioral analysis of ENU-induced Disc1-Q31L and -L100P mutant mice.ENU诱导的Disc1-Q31L和-L100P突变小鼠的综合行为分析
BMC Res Notes. 2012 Feb 20;5:108. doi: 10.1186/1756-0500-5-108.
8
Effects of antipsychotics on the behavioral deficits in human dominant-negative DISC1 transgenic mice with neonatal polyI:C treatment.抗精神病药对新生多聚肌苷酸处理的人类显性负 DISC1 转基因小鼠行为缺陷的影响。
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Abnormal interneuron development in disrupted-in-schizophrenia-1 L100P mutant mice.精神分裂症 1 号 DISC1 L100P 突变小鼠中异常中间神经元发育。
Mol Brain. 2013 Apr 30;6:20. doi: 10.1186/1756-6606-6-20.
10
DISC1 regulates lactate metabolism in astrocytes: implications for psychiatric disorders.DISC1 调控星形胶质细胞中的乳酸代谢：对精神疾病的影响。
Transl Psychiatry. 2018 Apr 12;8(1):76. doi: 10.1038/s41398-018-0123-9.

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Beyond vertebrates: as a model to study negative symptoms of schizophrenia.超越脊椎动物：作为研究精神分裂症阴性症状的模型。
Front Psychiatry. 2025 Jul 23;16:1622281. doi: 10.3389/fpsyt.2025.1622281. eCollection 2025.
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A Kpna1-deficient psychotropic drug-induced schizophrenia model mouse for studying gene-environment interactions.用于研究基因-环境相互作用的 Kpna1 缺陷型精神分裂症模型小鼠。
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DISC1 and reelin interact to alter cognition, inhibition, and neurogenesis in a novel mouse model of schizophrenia.在一种新型精神分裂症小鼠模型中，DISC1与reelin相互作用，以改变认知、抑制作用和神经发生。
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Prefrontal and Hippocampal Parvalbumin Interneurons in Animal Models for Schizophrenia: A Systematic Review and Meta-analysis.精神分裂症动物模型中海马和前额叶的 Parvalbumin 中间神经元：系统评价和荟萃分析。
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Behavioral analysis through the lifespan of mutant zebrafish identifies defects in sensorimotor transformation.对突变斑马鱼整个生命周期的行为分析揭示了感觉运动转换方面的缺陷。
iScience. 2023 Jun 14;26(7):107099. doi: 10.1016/j.isci.2023.107099. eCollection 2023 Jul 21.
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SELENBP1 overexpression in the prefrontal cortex underlies negative symptoms of schizophrenia.SELENBP1 在额叶皮层中的过度表达是精神分裂症阴性症状的基础。
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本文引用的文献

1
Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice.有证据表明，C57BL/6J小鼠中的许多DISC1异构体在129S6/SvEv小鼠中也有表达。
Mol Psychiatry. 2007 Oct;12(10):897-9. doi: 10.1038/sj.mp.4002024.
2
Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders.少突胶质细胞中erbB信号的缺失会改变髓鞘和多巴胺能功能，这是神经精神疾病的一种潜在机制。
Proc Natl Acad Sci U S A. 2007 May 8;104(19):8131-6. doi: 10.1073/pnas.0702157104. Epub 2007 May 1.
3
Behavioral phenotypes of Disc1 missense mutations in mice.小鼠中Disc1错义突变的行为表型。
Neuron. 2007 May 3;54(3):387-402. doi: 10.1016/j.neuron.2007.04.015.
4
PC12 cell model of inducible expression of mutant DISC1: new evidence for a dominant-negative mechanism of abnormal neuronal differentiation.突变型DISC1诱导表达的PC12细胞模型：神经元分化异常的显性负性机制的新证据
Neurosci Res. 2007 Jul;58(3):234-44. doi: 10.1016/j.neures.2007.03.003. Epub 2007 Mar 16.
5
Modeling madness in mice: one piece at a time.在小鼠身上模拟疯狂：一次研究一部分。
Neuron. 2006 Oct 5;52(1):179-96. doi: 10.1016/j.neuron.2006.09.023.
6
Transgenic mice expressing dominant-negative activin receptor IB in forebrain neurons reveal novel functions of activin at glutamatergic synapses.在前脑神经元中表达显性负性激活素受体IB的转基因小鼠揭示了激活素在谷氨酸能突触中的新功能。
J Biol Chem. 2006 Sep 29;281(39):29076-84. doi: 10.1074/jbc.M604959200. Epub 2006 Aug 2.
7
The genetics and biology of DISC1--an emerging role in psychosis and cognition.精神分裂症1号基因（DISC1）的遗传学与生物学——在精神病和认知方面的新作用
Biol Psychiatry. 2006 Jul 15;60(2):123-31. doi: 10.1016/j.biopsych.2006.04.008.
8
Differential expression of disrupted-in-schizophrenia (DISC1) in bipolar disorder.双相情感障碍中精神分裂症断裂基因1（DISC1）的差异表达
Biol Psychiatry. 2006 Nov 1;60(9):929-35. doi: 10.1016/j.biopsych.2006.03.032. Epub 2006 Jun 30.
9
A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions.精神分裂症相关基因1（DISC1）综述：神经发育、认知与精神疾病
Biol Psychiatry. 2006 Jun 15;59(12):1189-97. doi: 10.1016/j.biopsych.2006.03.065.
10
Genetic mouse models of schizophrenia: from hypothesis-based to susceptibility gene-based models.精神分裂症的基因小鼠模型：从基于假说的模型到基于易感基因的模型。
Biol Psychiatry. 2006 Jun 15;59(12):1180-8. doi: 10.1016/j.biopsych.2006.02.024. Epub 2006 May 2.

显性负性 DISC1 转基因小鼠表现出可通过适用于人类的检测方法检测到的精神分裂症相关表型。

Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans.

作者信息

Hikida Takatoshi, Jaaro-Peled Hanna, Seshadri Saurav, Oishi Kenichi, Hookway Caroline, Kong Stephanie, Wu Di, Xue Rong, Andradé Manuella, Tankou Stephanie, Mori Susumu, Gallagher Michela, Ishizuka Koko, Pletnikov Mikhail, Kida Satoshi, Sawa Akira

机构信息

Department of Psychiatry and Behavioral Sciences, Graduate Program in Cellular and Molecular Medicine, and Division of Neurobiology, The Johns Hopkins University, Baltimore, MD 21287, USA.

出版信息

Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. doi: 10.1073/pnas.0704774104. Epub 2007 Aug 3.

DOI:10.1073/pnas.0704774104
PMID:17675407
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1964873/
Abstract

Here, we report generation and characterization of Disrupted-In-Schizophrenia-1 (DISC1) genetically engineered mice as a potential model for major mental illnesses, such as schizophrenia. DISC1 is a promising genetic risk factor for major mental illnesses. In this transgenic model, a dominant-negative form of DISC1 (DN-DISC1) is expressed under the alphaCaMKII promoter. In vivo MRI of the DN-DISC1 mice detected enlarged lateral ventricles particularly on the left side, suggesting a link to the asymmetrical change in anatomy found in brains of patients with schizophrenia. Furthermore, selective reduction in the immunoreactivity of parvalbumin in the cortex, a marker for an interneuron deficit that may underlie cortical asynchrony, is observed in the DN-DISC1 mice. These results suggest that these transgenic mice may be used as a model for schizophrenia. DN-DISC1 mice also display several behavioral abnormalities, including hyperactivity, disturbance in sensorimotor gating and olfactory-associated behavior, and an anhedonia/depression-like deficit.

摘要

在此，我们报告了精神分裂症断裂基因-1（DISC1）基因工程小鼠的构建及特性研究，该小鼠可作为精神分裂症等主要精神疾病的潜在模型。DISC1是主要精神疾病中一个很有前景的遗传风险因素。在这个转基因模型中，一种显性负性形式的DISC1（DN-DISC1）在α钙调蛋白激酶II启动子的控制下表达。对DN-DISC1小鼠进行的活体磁共振成像检测到侧脑室扩大，尤其是左侧，这表明与精神分裂症患者大脑中发现的解剖结构不对称变化存在关联。此外，在DN-DISC1小鼠中观察到皮质小白蛋白免疫反应性选择性降低，小白蛋白是一种中间神经元缺陷的标志物，可能是皮质不同步的基础。这些结果表明，这些转基因小鼠可作为精神分裂症的模型。DN-DISC1小鼠还表现出多种行为异常，包括多动、感觉运动门控和嗅觉相关行为障碍，以及快感缺失/抑郁样缺陷。