Dysregulation of the Wnt/β-catenin signaling pathway via Rnf146 upregulation in a VPA-induced mouse model of autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social behavior and communication, repetitive behaviors, and restricted interests. In addition to genetic factors, environmental factors such as prenatal drug exposure contribute to the development of ASD. However, how those prenatal factors induce behavioral deficits in the adult stage is not clear. To elucidate ASD pathogenesis at the molecular level, we performed a high-resolution mass spectrometry-based quantitative proteomic analysis on the prefrontal cortex (PFC) of mice exposed to valproic acid (VPA) in utero, a widely used animal model of ASD. Differentially expressed proteins (DEPs) in VPA-exposed mice showed significant overlap with ASD risk genes, including differentially expressed genes from the postmortem cortex of ASD patients. Functional annotations of the DEPs revealed significant enrichment in the Wnt/β-catenin signaling pathway, which is dysregulated by the upregulation of Rnf146 in VPA-exposed mice. Consistently, overexpressing Rnf146 in the PFC impaired social behaviors and altered the Wnt signaling pathway in adult mice. Furthermore, Rnf146-overexpressing PFC neurons showed increased excitatory synaptic transmission, which may underlie impaired social behavior. These results demonstrate that Rnf146 is critical for social behavior and that dysregulation of Rnf146 underlies social deficits in VPA-exposed mice. Autism spectrum disorder: Improving understanding at the molecular level Increased levels of a protein that regulates neuronal signaling pathway, called Rnf146, are associated with social behavior deficits consistent with autism spectrum disorder (ASD) in a mouse model. Individuals with ASD show decreased sociability, repetitive behaviors, and restricted interests. Although both genetic and environmental factors are involved, the underlying molecular mechanisms are unclear. Yong-Seok Lee at Seoul National University in South Korea and co-workers investigated the mechanisms underlying ASD using a drug-induced mouse model. They found that the ASD-model mice showed deficits in social behaviors and had higher levels of Rnf146 compared to control mice. Boosting levels of Rnf146 in control mice produced ASD-like behavior. Further investigation showed that the ASD-model mice had increased excitatory synaptic transmission in the prefrontal cortex, which regulates social behavior. These results indicate a promising target for ASD research.