Systems Genetics Reveals the Gene Regulatory Mechanisms of in the Development of Autism Spectrum Disorders.

Background: Autism spectrum disorder (ASD) involves complex interactions between genetic and environmental factors. Recent studies suggest that dysregulation of β-arrestin2 () in the central nervous system is linked to ASD. However, its specific mechanisms remain unknown.

Methods: This study employs a systems genetics approach to comprehensively investigate in multiple brain tissues, including the amygdala, cerebellum, hippocampus, and prefrontal cortex, using BXD recombinant inbred (RI) strains. In addition, genetic variance analysis, correlation analysis, expression quantitative trait loci (eQTL) mapping, and functional annotation were used to identify the key downstream targets of , validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB).

Results: exhibited expression variations across the four brain regions in BXD mice. eQTL mapping revealed that is cis-regulated, and increased expression levels were significantly correlated with ASD-like symptoms, such as impaired social interactions and abnormal learning and memory. Furthermore, protein-protein interaction (PPI) network analysis, tissue correlation, functional relevance to autism, and differential expression identified eight downstream candidate genes regulated by . The experimental results demonstrated that deletion of led to the downregulation of , , and expression, along with protein kinase A (PKA)-induced hyperactivation of Synapsin I. These findings suggest that may contribute to the pathogenesis of autism by modulating the expression of these genes.

Conclusions: This study highlights the role of in ASD pathogenesis and identifies , , and as key downstream regulators. These findings provide new insights into the molecular mechanisms of ASD and pave the way for novel therapeutic targets.