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GABRB3 and Placental Vulnerability in ASD

ASD 中的 GABRB3 和胎盘脆弱性

基本信息

批准号：
8438258
负责人：
Theo D Palmer
金额：
$ 52.38万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8438258
关键词：
Agonist Alleles Angelman Syndrome Attention Attenuated Autistic Disorder Behavioral Benign Blood Vessels Brain Cells Child Chromosome abnormality Chromosomes Cytogenetics Cytokine Signaling Data Defect Development Environmental Risk Factor Event Exploratory Behavior Fetus Future GABA-A Receptor Genes Genetic Genetic Models Genetic Predisposition to Disease Hemorrhage Hypoxia Immune Immune response Immune system Incidence Infection Inflammation Inheritance Patterns Intervention Lead Lipopolysaccharides Live Birth Modeling Mothers Mus Neurological outcome Neurons Pathology Patients Perfusion Peripheral Pervasive Development Disorder Phenotype Placenta Prader-Willi Syndrome Pregnancy Regulation Rett Syndrome Risk Risk Factors Role Socialization Testing Tissues Work autism spectrum disorder cytokine fetal fetus at risk gamma-Aminobutyric Acid gene environment interaction immune activation immune function loss of function novel offspring prenatal prevent public health relevance receptor research study response

项目摘要

DESCRIPTION (provided by applicant): The GABA(A) receptor ¿3 subunit gene GABRB3 has been strongly implicated in the pervasive developmental disorders (PDD). GABRB3 lies within chromosome 15q11-13, and anomalies in this region are associated with Rett syndrome, Prader-Willi syndrome, Angelman Syndrome, and are the single most frequent cytogenetic abnormality found in the autism spectrum disorders (ASD). It has recently been recognized that peripheral GABA(A) receptors are involved in immune cell regulation and that activation of GABA(A) receptors can attenuate tissue inflammation. Maternal inflammation during pregnancy has been an environmental factor associated with ASD and we have found that loss of one GABRB3 allele in mother and fetus is sufficient to markedly increase placental pathology in response to cytokines produced by a mild maternal innate immune response in mice. In contrast, activating GABA(A) receptors during a maternal immune event attenuates the impact to the fetus. This implicates GABA(A)-related immune alterations and placental vulnerability as a potential gene-environment interaction which is associated with increased risk of ASD and other PDDs. Importantly, the maternal inheritance pattern of 15q11-13 anomalies suggests that GABA(A)-related immune functions may be altered in mother, as well as in the placenta and fetus. The experiments proposed here test whether selective loss of GABARB3 in the mother, placenta or fetus increase the risk of developing autistic features in offspring following a prenatl maternal immune event.

描述（由申请人提供）：GABA（A）受体3亚单位基因GABRB 3与广泛性发育障碍（PDD）密切相关。GABRB 3位于染色体15 q11 -13内，该区域的异常与Rett综合征、Prader-Willi综合征、Angelman综合征相关，并且是在自闭症谱系障碍（ASD）中发现的单一最常见的细胞遗传学异常。最近已经认识到外周GABA（A）受体参与免疫细胞调节，并且GABA（A）受体的活化可以减轻组织炎症。妊娠期间的母体炎症是与ASD相关的环境因素，并且我们已经发现母亲和胎儿中的一个GABRB 3等位基因的丢失足以显著增加胎盘病理学，以响应由小鼠中的轻度母体先天免疫应答产生的细胞因子。相反，在母体免疫事件期间激活GABA（A）受体会减弱对胎儿的影响。这表明GABA（A）相关的免疫改变和胎盘脆弱性是一种潜在的基因-环境相互作用，与ASD和其他PDD的风险增加有关。重要的是，15 q11 -13异常的母体遗传模式表明，母亲以及胎盘和胎儿的GABA（A）相关免疫功能可能会改变。本文提出的实验测试母体、胎盘或胎儿中GABARB 3的选择性缺失是否会增加产前母体免疫事件后后代发展自闭症特征的风险。