REELIN DEFICIENCY--MODEL FOR SCHIZOPHRENIA VULNERABILITY

REELIN 缺陷——精神分裂症脆弱性模型

基本信息

批准号：
6794080
负责人：
ALESSANDRO GUIDOTTI
金额：
$ 27.18万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2006-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6794080
关键词：
aging behavior test brain mapping developmental genetics developmental neurobiology gamma aminobutyrate gene targeting genetic models genetic susceptibility haploidy laboratory mouse mature animal newborn animals schizophrenia

项目摘要

DESCRIPTION: (Adapted from the Investigator's Abstract) Telencephalic brain structures are known to follow an unusually complex course of embryological developmental in which RELN plays a pivotal signaling role. In this project, we want to establish whether in postnatal and adult mice genetic RELN deficiency (RELN haploinsufficiency) leads to the expression of progressive and region-specific brain abnormalities and whether some of the abnormalities resemble caricatures of the alterations observed in the brain of schizophrenic patients. We have selected the heterozygous reeler mutant (rl +/-) mouse as a model of RELN haploinsufficiency. In preliminary experiments we have shown that in adult rl +/- mice, in addition to a lower than normal RELN expression there are a number of microanatomical and neurophysiological abnormalities reminiscent of schizophrenia. Thus, we propose to 1) compare whether RELN expression and neuronal location are similar in rl +/- and wild-type (wt) mice; 2) determine whether RELN haploinsufficiency elicits changes in the relationship existing between RELN haploinsufficiency and altered cortical distribution of GABAergic interneurons, decrease of GAD67 expression and decrease in neuropil density; 3) study if there is a progression of these changes with age, or if these changes are restricted to cortex or are present in other brain areas that are also affected in schizophrenia; and 4) examine if RELN haploinsufficiency is a vulnerability factor that predisposes peripubertal mice to an incidence of behavioral and microanatomical abnormalities when exposed to noxious insults such as social isolation stress. Although the putative interaction of RELN haploinsufficiency with epigenetic factors occurring in schizophrenic patients probably differs from the factors operative in socially isolated mice, study of the murine model may reveal those mechanisms of neurodevelopment that are likely to be disrupted by RELN deficiency in the brain of schizophrenic patients. The understanding of RELN expression regulation in adult brain may be of great importance in the design of pharmacological tools to correct RELN brain insufficiency and to reduce the behavioral and microanatomical abnormalities associated to this deficiency.

描述：（改编自调查员的摘要）端脑大脑已知结构遵循异常复杂的胚胎学过程 Reln起关键信号传导作用的发展。在这个项目中，我们想要确定在产后和成年小鼠中是否遗传缺乏症（RELN单倍度不足）导致进行性和区域特异性的脑异常以及某些异常是否类似于精神分裂症大脑中观察到的改变的漫画患者。我们已经选择了杂合子卷轴突变体（RL +/-）小鼠 Reln单倍不足的模型。在初步实验中，我们已经表明在成年RL +/-小鼠中，此外，那里的reln表达低于正常人是许多微解剖学和神经生理异常让人联想到精神分裂症。因此，我们建议1）比较是否 RL +/-和野生型（WT）小鼠的表达和神经元位置相似。 2）确定Reln单倍不足是否引起了 Reln单倍不足和皮质改变之间存在的关系 GABA能中间神经元的分布，GAD67表达的降低和降低神经质密度； 3）研究是否有进展随着年龄的增长或这些更改仅限于皮层或存在的变化在精神分裂症中也受到影响的其他大脑区域； 4）检查是否 Reln单倍不足是一种容易体现围角的脆弱因素当小鼠发生行为和微解剖异常的发生率时暴露于有害侮辱，例如社会隔离压力。虽然RELN单倍不足与表观遗传学的假定相互作用精神分裂症患者发生的因素可能与因素不同在社会孤立的小鼠中的手术，对鼠模型的研究可能会揭示这些模型神经发育机制可能会因reln而破坏精神分裂症患者大脑缺乏。对Reln的理解成人大脑中的表达调节在设计中可能非常重要纠正脑部不足并减少的药理学工具与这种缺陷相关的行为和微解剖异常。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

REELIN and schizophrenia: a disease at the interface of the genome and the epigenome.

DOI：
10.1124/mi.2.1.47
发表时间：
2002-02-01
期刊：
Molecular interventions
影响因子：
0
作者：
Costa, E;Chen, Y;Guidotti, A
通讯作者：
Guidotti, A

GABAergic cortical neuron chromatin as a putative target to treat schizophrenia vulnerability.

DOI：
10.1615/critrevneurobiol.v15.i2.20
发表时间：
2003-01-01
期刊：
Critical Reviews in Neurobiology
影响因子：
0
作者：
Costa, Erminio;Grayson, Dennis R.;Guidotti, Alessandro
通讯作者：
Guidotti, Alessandro

Epigenetic downregulation of GABAergic function in schizophrenia: potential for pharmacological intervention?

DOI：
10.1124/mi.3.4.220
发表时间：
2003-06-01
期刊：
Molecular interventions
影响因子：
0
作者：
Costa, Erminio;Grayson, Dennis R;Guidotti, Alessandro
通讯作者：
Guidotti, Alessandro

Immunocytochemical localization of reelin in the olfactory bulb of the heterozygous reeler mouse: an animal model for schizophrenia.

杂合子 reeler 小鼠嗅球中 reelin 的免疫细胞化学定位：精神分裂症动物模型。

DOI：
10.1179/016164103771953916
发表时间：
2003
期刊：
Neurological research.
影响因子：
0
作者：
Pappas,GeorgeD;Kriho,Virginia;Liu,Wen-Sheng;Tremolizzo,Lucio;Lugli,Giovanni;Larson,John
通讯作者：
Larson,John

Chromatin, DNA methylation and neuron gene regulation--the purpose of the package.

染色质、DNA 甲基化和神经元基因调控——该包的目的。