Cellular mechanism of Arid1b haploinsufficiency-associated social deficit

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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.