Summary: A collaborative research project has advanced our understanding of how environmental factors can influence the onset of autism spectrum disorder (ASD). Using a valproate (VPA)-induced mouse model, the research team found increased expression of the Rnf146 gene in the prefrontal cortex, a change linked to autistic-like behaviors and altered neurotransmitter balance in the frontal lobe.
These molecular and behavioral findings mirror abnormalities reported in other ASD models and point toward common mechanisms that could inform earlier diagnosis and new treatment strategies.
Key Facts:
- Valproate exposure in utero elevates Rnf146 expression in the prefrontal cortex of a mouse ASD model, implicating this gene in ASD-related changes.
- The VPA-treated mice exhibited an imbalance between excitatory and inhibitory neurotransmission in the frontal lobe, a characteristic shared with other autism models.
- The study was funded by the Ministry of Science and ICT and published in Experimental & Molecular Medicine in August 2023.
Source: DGIST
The research team led by Professor Minsik Kim in DGIST’s Department of New Biology announced on the 17th that, in partnership with teams led by Professors Yongsuk Lee (Seoul National University), Junyong Ahn (Korea University), and Chanyeong Shin (Konkuk University), they have identified environmental factors that influence mechanisms underlying autism spectrum disorder.
Autism spectrum disorder is a neurodevelopmental condition typically emerging in early childhood, marked by challenges in social communication and interaction, repetitive behaviors, and restricted interests. Current estimates suggest ASD affects roughly 1 in 50 to 1 in 60 children, underscoring its relative prevalence and the urgency of improved understanding.
While genetic contributors to ASD are well documented, environmental influences—particularly prenatal exposures—also play a critical role. Prior work from Professor Chanyeong Shin’s group at Konkuk University implicated prenatal exposure to valproate, a medication sometimes used during pregnancy, as a potential risk factor for altered fetal brain development and later ASD-like traits. However, therapeutic development has been limited by incomplete knowledge about the molecular targets involved.
To address that gap, Professor Minsik Kim’s team and collaborators applied multi-omics analyses to the VPA-induced mouse model developed by Professor Shin. Combining proteomics, transcriptomics, and functional studies allowed the researchers to identify molecular changes in the prefrontal cortex (PFC) associated with prenatal VPA exposure.
Their analyses revealed significant upregulation of the Rnf146 gene in the PFC of VPA-exposed mice. Rnf146 is linked to regulation of the Wnt/β-catenin signaling pathway, a pathway the team found dysregulated in the VPA model. In complementary experiments led by Professor Yongsuk Lee’s group at Seoul National University, overexpression of Rnf146 in the PFC reproduced autistic-like social impairments in adult mice and altered synaptic function.
Electrophysiological and synaptic measurements indicated increased excitatory synaptic transmission in neurons overexpressing Rnf146, tipping the balance of excitation and inhibition in the frontal lobe. Professor Lee noted that this excitatory/inhibitory imbalance is a recurring feature across multiple ASD models, reinforcing the idea that dysregulation of common molecular pathways contributes to social deficits.
Collectively, these findings support a model in which prenatal environmental exposure (VPA) leads to Rnf146 upregulation, disruption of Wnt/β-catenin signaling, synaptic imbalance, and subsequent social behavior deficits. The identification of Rnf146 and associated pathways provides concrete molecular targets for future study and potential intervention.
Professor Kim emphasized the next steps: “We will extend multi-omics studies across diverse developmental disorder models in collaboration with other institutions, aiming to map core networks driving ASD and to pinpoint therapeutic targets.” Professor Shin added that the results lay groundwork for exploring how environmental pollutants or prenatal exposures might contribute to ASD. Professor Ahn highlighted the power of multi-omics to reveal novel molecular networks and regulatory genes important for brain development and ASD.
By linking an environmental insult to specific molecular and synaptic changes in the prefrontal cortex, this study advances mechanistic understanding of ASD and may support improved early detection and targeted therapies in the future.
This research was supported by the Ministry of Science and ICT and published in Experimental & Molecular Medicine on August 1, 2023.
About this autism research news
Author: Wankyu Lim
Source: DGIST
Contact: Wankyu Lim – DGIST
Image: Image credited to Neuroscience News
Original Research: Closed access.
“Dysregulation of the Wnt/β-catenin signaling pathway via Rnf146 upregulation in a VPA-induced mouse model of autism spectrum disorder” by Minsik Kim et al., Experimental & Molecular Medicine.
Abstract
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 condition characterized by impaired social behavior and communication, repetitive behaviors, and restricted interests. Beyond genetic risks, prenatal environmental factors—such as exposure to certain drugs—can increase ASD risk, but the molecular mechanisms linking those exposures to adult behavioral deficits remain unclear.
To investigate, the authors performed high-resolution, mass spectrometry-based quantitative proteomics on the prefrontal cortex of mice exposed to valproic acid in utero, a commonly used ASD animal model. Differentially expressed proteins in VPA-exposed mice significantly overlapped with known ASD risk genes and with gene expression changes observed in postmortem ASD cortex samples.
Functional analyses highlighted enrichment in the Wnt/β-catenin signaling pathway, driven in part by upregulation of Rnf146 in VPA-exposed mice. Overexpression of Rnf146 in the PFC produced impaired social behavior and Wnt pathway alterations in adult mice, and neurons overexpressing Rnf146 showed increased excitatory synaptic transmission—providing a plausible synaptic mechanism for observed social deficits.
These results indicate that Rnf146 is critical for normal social behavior and that its dysregulation contributes to social impairments in the VPA model of ASD.