GABRB3 and Placental Vulnerability in ASD

GABA(A)受体¿3亚基基因GABRB3与广泛性发育障碍（PDD）密切相关。GABRB3位于染色体15q11-13内，该区域的异常与Rett综合征、Prader-Willi综合征、Angelman综合征有关，是自闭症谱系障碍（ASD）中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，GABA(A)受体的激活可以减轻组织炎症。妊娠期间的母体炎症一直是与ASD相关的环境因素，我们发现母亲和胎儿中GABRB3等位基因的缺失足以显著增加胎盘病理，以响应小鼠母体温和先天免疫反应产生的细胞因子。相反，在母体免疫事件中激活GABA(A)受体会减弱对胎儿的影响。这意味着GABA(A)相关的免疫改变和胎盘易感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，15q11-13异常的母体遗传模式表明，GABA(A)相关的免疫功能可能在母体以及胎盘和胎儿中发生改变。本文提出的实验测试了GABARB3在母体、胎盘或胎儿中的选择性缺失是否会增加胎儿在产前母体免疫事件后出现自闭症特征的风险。

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.