Cellular mechanism of Arid1b haploinsufficiency-associated social deficit

项目摘要 自闭症谱系障碍（ASD）的特征是社会互动和沟通受损， 重复的行为虽然ASD行为被很好地描述，但其背后的病理机制 发育情况仍不清楚。没有药理学和/或遗传学预防或治疗方法 自闭症治疗工具的开发需要鉴定致病因素及其细胞毒性。 大脑中的机制。最近的遗传学研究表明，AT丰富的交互作用的单倍不足， 结构域1B（ARID 1B）基因导致ASD和智力残疾，这表明ARID 1B可能在ASD和智力残疾中起关键作用。 在社会行为控制中的作用。尽管据报道ARID 1B单倍不足会导致ASD， ARID 1B功能障碍如何导致ASD患者的异常社会行为。为了应对这一挑战，我们 建立了一个ARID 1B单倍不足的小鼠模型，发现这只小鼠表现出社会缺陷， 再现人类ASD表型。我们的目标是确定ARID 1B的细胞机制 haploinformation-induced社会deficits赤字.先前的研究表明，腹侧被盖区之间的大脑回路 腹侧被盖区（VTA）和丘脑核（NAc）调节社会行为。它们也显示了 ASD和线粒体缺陷。此外，研究表明Arid 1b单倍不足与 线粒体功能障碍在我们的初步调查中，我们发现VTA到NAc的连接是 与野生型对照组相比，Arid 1b单倍不足小鼠中减少。此外，我们还观察到功能性 Arid 1b ASD小鼠模型中线粒体的改变和活性氧的过度产生。 线粒体相关基因在Arid 1b模型中下调。根据我们的初步发现 结合以前的研究，我们假设VTA-NAc回路中的干扰在 Arid 1b单倍缺陷小鼠社会缺陷和线粒体缺陷是社会改变的基础。 使用小鼠遗传学，病毒介导的电路操作，电生理评估， 人类iPSC研究和分子/生物化学方法，我们将在小鼠中测试这些想法， 通过检查以下相关目的来建立人类模型：目的1）检查中脑边缘回路在以下方面的作用： Arid 1b单倍型缺陷小鼠社会行为;目的2）检测线粒体功能障碍作为细胞 Arid 1b单倍体缺陷诱导的中脑边缘异常的机制;目的3）鉴定Arid 1b单倍体缺陷诱导的中脑边缘异常的分子机制。 Arid 1b单倍不足中线粒体功能障碍的潜在机制我们的研究可能提供新的 对ASD中与脑回路改变和线粒体功能障碍相关的社会缺陷的机械见解。

Project Summary Autism spectrum disorder (ASD) is characterized by impaired social interaction and communication as well as repetitive behavior. While ASD behaviors are well described, the pathological mechanism underlying this developmental condition remains unknown. There are no pharmacological and/or genetic preventions or cures for ASD. Development of therapeutic tools requires identification of causative factors and their cellular mechanisms in the brain. Recent genetic studies have shown that haploinsufficiency of the AT-rich interactive domain 1B (ARID1B) gene causes ASD and intellectual disability, suggesting that ARID1B may play a critical role in social behavior control. Although ARID1B haploinsufficiency reportedly causes ASD, nothing was known about how ARID1B dysfunction leads to abnormal social behavior in ASD. In response to this challenge, we generated a mouse model of ARID1B haploinsufficiency and found that this mouse displays social deficits recapitulating human ASD phenotypes. Our goal is to identify the cellular mechanism of ARID1B haploinsufficiency-induced social deficits. Prior studies show that the brain circuit between the ventral tagmental area (VTA) and nucleus accumbens (NAc) regulates social behavior. They also present a strong link between ASD and mitochondrial defects. Furthermore, studies suggest an association of Arid1b haploinsufficiency with mitochondrial dysfunction. In our preliminary investigation, we found that the VTA-to-NAc connection was reduced in Arid1b haploinsufficient mice compared to wild-type controls. Additionally, we observed functional alterations of mitochondria and overproduction of reactive oxygen species in the Arid1b mouse model of ASD. Mitochondria-associated genes were downregulated in the Arid1b model. Based on our preliminary findings combined with previous studies, we hypothesize that disturbance in the VTA-NAc circuit plays a key role in social deficits in Arid1b haploinsufficient mice and that mitochondrial defects underlie the social alteration. Using a combination of mouse genetics, virus-mediated circuit manipulation, electrophysiological assessment, human iPSC investigation, and molecular/biochemical approaches, we will test these ideas in mouse and human models by examining the following related aims: Aim 1) Examine the role of the mesolimbic circuit in social behavior in Arid1b haploinsufficient mice; Aim 2) Examine mitochondrial dysfunction as a cellular mechanism of Arid1b haploinsufficiency-induced mesolimbic abnormality; Aim 3) Identify the molecular mechanism underlying mitochondrial dysfunction in Arid1b haploinsufficiency. Our study may provide novel mechanistic insights into social deficits in ASD related to brain circuit alteration and mitochondrial dysfunction.