Summary: A collaborative research effort delved deeper into the environmental factors impacting autism spectrum disorder (ASD) onset. Utilizing a mouse model treated with valproate, researchers observed an increase in the expression of the Rnf146 gene, a known ASD influencer, in the mouse’s prefrontal lobe.
This was associated with autistic behavioral patterns and a disrupted neurotransmitter balance in the frontal lobe, a phenomenon seen across various ASD models. The findings pave the way for improved ASD understanding, early detection, and treatment approaches.
Key Facts:
- The Rnf146 gene, influenced by valproate exposure, plays a pivotal role in autism, as demonstrated in the mouse model.
- The observed neurotransmitter imbalance in the frontal lobe of the mouse model mirrors what is typically seen in other autism models.
- Funded by the Ministry of Science and ICT, this groundbreaking research was published in “Experimental & Molecular Medicine” in August 2023.
Source: DGIST
The research team led by Professor Minsik Kim from the Department of New Biology at DGIST (President Kuk Yang) announced on the 17th (Thurs.) that they have identified the environmental factors affecting the occurrence mechanism of autism spectrum disorder through a joint study conducted along with the research teams led by Professor Yongsuk Lee at Seoul National University, Professor Junyong Ahn at Korea University, and Chanyeong Shin at Konkuk University.
Autism spectrum disorder is a neurodevelopmental disorder that typically occurs in early childhood, in which behavioral patterns, interests, and activity range are restricted and repeated due to the inability to perform normal social communications and interactions. According to certain studies, 1 out of every 50 to 60 children has a spectrum disorder, making them fairly common.
Autism spectrum disorder is known to be caused by genetic factors as well as various environmental factors such as severe infection or exposure to specific types of drugs during pregnancy.
Meanwhile, a previous study conducted by the research team of Professor Chan-yeong Shin at Konkuk University discovered that valproate may be potentially related to autism spectrum disorder since it may affect the brain development of a fetus when used during pregnancy. However, the development of therapeutic drugs has faced challenges due to a lack of research on the molecular target.
Thus, the research team of Professor Minsik Kim performed a multi-omics analysis with Professor Ahn’s research team at Korea University using the mouse model treated with valproate developed by Professor Shin’s research team.
The results showed that expression of the Rnf146 gene, which is known to affect autism spectrum disorder, increased in the prefrontal lobe of the autism mouse model due to an adverse reaction to valproate. Furthermore, autistic behavioral patterns were observed using the Rnf146 gene expression model in a joint effort with Professor Lee’s research team at the College of Medicine of Seoul National University.
It was discovered that the balance between excitatory and inhibitory neurotransmitters was disturbed in the frontal lobe of the mouse model. Professor Lee of Seoul National University said,
“Since this phenomenon is commonly observed in other autistic models, this research significantly contributes to identifying the common cause of autism.”
The findings of this study are expected to help further understand the mechanism related to autism spectrum disorder, and even contribute to advancing early detection and treatment methods for autism spectrum disorder.
Professor Kim said, “We will continue our research on various developmental disorder models using multi-omics analysis through joint studies with other institutions and carry out comprehensive research on model organisms so as to identify the core network of autism spectrum disorder and discover treatment targets.”
Professor Shin of Konkuk University added, “The research results are expected to become the foundation of future research on the possibility of environmental pollution causing autism and the related mechanisms.”
Professor Ahn of Korea University stated, “In particular, the multi-omics technology is expected to be widely utilized in discovering a new molecular network in the brain development process and finding critical regulatory genes of various autistic models.”
The findings of this research, funded by the Ministry of Science and ICT, were published in “Experimental & Molecular Medicine” (IF 12.800, JCR 4.8%) on August 1, 2023.
About this autism research news
Author: Wankyu Lim
Source: DGIST
Contact: Wankyu Lim – DGIST
Image: The image is 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 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.
