Effects of maternal immune activation on GABRB3-deficient neocortical progenitors

 描述（由申请人提供）：在美国，每68名活产婴儿中就有1名被诊断出患有自闭症谱系障碍（ASD），这被认为是增长最快的儿童神经精神疾病之一。ASD是一种神经发育障碍，其特征是社会互动缺陷和重复或刻板行为。双胞胎研究和连锁分析证实，遗传异常和环境易感性有助于ASD。人类流行病学研究支持母亲暴露于环境风险（如产前感染）会显着增加后代患ASD的风险。妊娠早期异常的母体免疫激活（MIA）导致发育中胎儿中枢神经系统（CNS）的有害结果。作为一个关键的母胎界面，胎盘在免疫监视和胎儿生长中也起着关键作用，胎盘损伤与神经发育疾病的风险密切相关。我们已经确定了胎盘对脂多糖（LPS，一种模拟细菌感染的化合物）的脆弱性，该脂多糖由GABA受体A型（GABAAR）调节。有趣的是，各种GABAAR亚型不仅在CNS中表达，而且在免疫细胞和其他组织中表达，其中发现GABA信号传导调节免疫应答。在ASD病例中发现的最常见的GABAAR异常是位于15 q11 -13的母系遗传拷贝数变异（CNV），其与ASD、Angelman综合征、Prader Willi综合征有关。我的研究重点是新的ASD风险机制，涉及GABAAR之一，GABRB 3和MIA在ASD小鼠模型中的基因-环境相互作用。我推测，母系遗传的GABRB 3和MIA的部分丢失可能会加剧胎儿病理性脑表型。我将确定GABRB 3和MIA是否在早期发育中对神经祖细胞（NPC）功能产生协同不良影响。以前，我们证明，产前LPS的挑战导致皮质图案的变化在后代的Satb 2表达的上层胼胝体神经元和神经元层的形成在早期新皮质发育的丰度显着的影响。初步数据表明，Gabrb 3功能的部分丧失大大增加了LPS暴露后的胎盘损伤。短期目标是确定母亲或母体免疫细胞中的GABAAR功能是否是这种效应的基础。从长远来看，我将评估GABAAR是否是ASD小鼠模型中有效的药物靶点。证实母体GABAAR的改变会增加ASD表型的风险，也可能导致新的诊断方法，可以识别怀孕期间有风险的母亲。从这项拟议的研究中，我希望找到GABRB 3介导的遗传易感性与MIA相结合的下游关键候选分子。重要的是，针对这些关键介体分子的拮抗剂或中和抗体的施用可以恢复GABA-MIA轴的正常功能，这可能潜在地为降低ASD风险的治疗策略提供关键的见解。

 DESCRIPTION (provided by applicant): With diagnoses at 1 in 68 live births in the United States, autism spectrum disorders (ASD) have been considered one of the most increasing child neuropsychiatric diseases. ASD is a neurodevelopmental disability characterized by social interaction deficits and repetitive or stereotyped behaviors. Twin studies and linkage analysis confirm that genetic abnormalities and environmental susceptibilities contribute to ASD. Human epidemiological studies support that maternal exposure to environmental risks like prenatal infection significantly increases the risk for ASD in offspring. Abnormal maternal immune activation (MIA) during early pregnancy results in deleterious outcomes in the central nervous system (CNS) of the developing fetus. As a critical maternal-fetal interface, the placenta also plays a key role in immune surveillance as well as fetal growth, and placental injury is strongly associated with risks for neurodevelopmental disease. We have identified a placental vulnerability to lipopolysaccharide (LPS, a compound that mimics bacterial infections) that is modulated by GABA receptor type A (GABAAR). Intriguingly, various GABAAR subtypes are expressed not only in CNS but also in immune cells and other tissues, where GABA signaling is found to modulate immune response. The most common GABAAR anomaly found in ASD cases is a maternally inherited copy number variation (CNV) at 15q11-13 which is implicated in ASD, Angelman syndrome, Prader Willi syndrome. My studies focus on novel ASD-risk mechanisms involving gene-environment interaction between one of the GABAARs, GABRB3, and MIA in an ASD mouse model. I hypothesize that a maternally inherited partial loss of GABRB3 and MIA could exacerbate fetal pathological brain phenotypes. I will determine if GABRB3 and MIA generate synergistic adverse effects on neural progenitor cell (NPC) functions in early development. Previously, we demonstrated that prenatal LPS challenge causes cortical patterning alterations in offspring with a pronounced effect on the abundance of Satb2-expressing upper layer callosal neurons and neuronal layer formation during early neocortical development. Preliminary data suggest that partial loss of Gabrb3 function greatly increases placental damage following LPS exposure. A short-term goal is to determine if GABAAR function in mother or maternal immune cells underlies this effect. In the long-term, I will assess whether GABAARs are valid drug targets in a mouse model of ASD. Confirmation that alterations in maternal GABAARs increase risk of ASD phenotypes may also lead to novel diagnostics that can identify mothers at risk during pregnancy. From this proposed study, I expect to find the key candidate molecules working downstream of GABRB3-mediated genetic predisposition combined with MIA. Importantly, administration of antagonists or neutralizing antibodies against these key mediator molecules may restore normal function of the GABA-MIA axis, which may potentially provide critical insight into therapeutic strategies to reduce risk of ASD.