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Genetic expression alteration in autism model rats created by fetal teratogen-exposure

胎儿致畸剂暴露造成的自闭症模型大鼠的基因表达改变

基本信息

批准号：
17500247
负责人：
NARITA Naoko
金额：
$ 2.24万
依托单位：
Bunkyo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17500247/
关键词：
development and differentiation serotonin DNA microarray

项目摘要

Autism is a congenital neurological disorder characterized by impairment of socialization, abnormalities of communication, and limited activity and curiosity. We have recently established autism model rats by exposing embryonic day (E) 9 rat embryo to either thalidomide or valproic acid. Significant increase of hippocampal serotonin, frontal cortex dopamine, and hyperserotonemia was observed in the E9 teratogen-exposed rats when observed around postnatal day 50. In the present study, we have examined mRNA expression of various genes in the model rats and compared with control rats, to see what is the ontogene of this model rats.First we focused on the function of serotonin transporter (5-HTT) in the autism model rat 5-HTT controls reuptake of a neurotransmitter serotonin from the extracellular space, and regulates the duration and strength of the interactions between serotonin and its receptors. We have analyzed the mRNA expression level in the E9 thalidomide exposed embryos on E11,E13, and E15. Relative mRNA expression of 5-111T gene was decreased in the thalidomide exposed embryos on E13, but increased on E15, compared to the controls. Next we performed DNA microarray of mRNA extracted from hippocampus of autism model rats and controls on P20, 30, 40 and 50, and compared over 600 neuro-related gene expression. Many changes were found including change in dopaminergic receptor expression, which is intriguing when considering increase of dopamine concentration in the hippocampus of adult autism model rats. Other genetic expression, including membrane trafficking genes, growth factors, transcription factors, were found, and future precise investigation is necessary to determine when and what genetic cascade is responsible for the characteristic social defect found in autism in humans.

自闭症是一种先天性神经疾病，其特征是社交障碍、交流异常、活动和好奇心有限。我们最近通过将胚胎第9天的大鼠胚胎暴露于沙利度胺或丙戊酸，建立了自闭症大鼠模型。在出生后50天左右观察到，暴露于E9畸胎原的大鼠的海马区5-羟色胺、额叶皮质多巴胺和高5-羟色胺血症显著增加。在本研究中，我们检测了模型大鼠各种基因的mRNA表达，并与对照组大鼠进行了比较，以了解该模型大鼠的本体基因是什么。首先，我们重点研究了自闭症模型大鼠5-羟色胺转运体(5-HTT)的功能，5-HTT控制着神经递质5-羟色胺从细胞外间隙的重新摄取，并调节5-羟色胺与其受体相互作用的持续时间和强度。我们分析了E9沙利度胺暴露的胚胎在E11、E13和E15的mRNA表达水平。与对照组相比，暴露于E13的沙利度胺组胚胎中5-111T基因的相对mRNA表达在E13时降低，而在E15时增加。接下来，我们对自闭症模型大鼠和对照组在P20、30、40和50天的海马区提取的mRNA进行了DNA微阵列，比较了600多个神经相关基因的表达。发现了许多变化，包括多巴胺能受体表达的变化，当考虑到成年自闭症模型大鼠海马区多巴胺浓度的增加时，这一变化令人好奇。还发现了包括膜运输基因、生长因子、转录因子在内的其他基因表达，未来有必要进行精确的研究，以确定自闭症中发现的特有的社会缺陷是何时以及什么遗传级联反应造成的。