Does an ancient virus genome drive autism?
Although autism is a common neurodevelopmental disorder, the multiple factors behind its onset are still not fully understood. Animal models of idiopathic autism, especially mice, are often used to help researchers understand ...
Now, an international research collaboration including Kobe University's Professor Takumi Toru and Researcher Chia-wen Lin and colleagues have made new discoveries regarding autism onset in mouse models.
In their detailed series of experiments and analyses of BTBR/J mice and the other subspecies BTBR/R, they revealed that endogenous retrovirus activation increases a fetus's susceptibility to autism. They also discovered that BTBR/R exhibits autistic-like behaviors without reduced learning ability, making it a more accurate model of autism than the widely-used BTBR/J model. These research results were published in Molecular Psychiatry on March 7, 2023.
In their detailed series of experiments and analyses of BTBR/J mice and the other subspecies BTBR/R, they revealed that endogenous retrovirus activation increases a fetus's susceptibility to autism. They also discovered that BTBR/R exhibits autistic-like behaviors without reduced learning ability, making it a more accurate model of autism than the widely-used BTBR/J model. These research results were published in Molecular Psychiatry on March 7, 2023.
It is hoped that further research will contribute towards better classification of autism types, as well as the creation of new treatment strategies for neurodevelopmental disorders.
Autism (autism spectrum disorder) is a neurodevelopmental disorder that remains largely unexplored despite the rapidly increasing number of patients. Reasons for this continuing increase in people diagnosed with autism include changes to diagnostic criteria and older fathers becoming more common.
Autism is strongly related to genetic factors and can be caused by abnormalities in DNA structure, such as copy number variations. Animal models, especially mice, are often used in research to illuminate the pathology of autism. Among these models, BTBR/J is a mouse model of the natural onset of autism that is commonly used. Studies have reported various abnormalities in BTBR/J mice including impairment of the corpus callosum (which connects the left and right hemispheres of the brain) and excessive immune system signaling. However, it is not fully understood why this particular lineage displays autistic-like behavioral abnormalities.
Autism (autism spectrum disorder) is a neurodevelopmental disorder that remains largely unexplored despite the rapidly increasing number of patients. Reasons for this continuing increase in people diagnosed with autism include changes to diagnostic criteria and older fathers becoming more common.
Autism is strongly related to genetic factors and can be caused by abnormalities in DNA structure, such as copy number variations. Animal models, especially mice, are often used in research to illuminate the pathology of autism. Among these models, BTBR/J is a mouse model of the natural onset of autism that is commonly used. Studies have reported various abnormalities in BTBR/J mice including impairment of the corpus callosum (which connects the left and right hemispheres of the brain) and excessive immune system signaling. However, it is not fully understood why this particular lineage displays autistic-like behavioral abnormalities.
Fig. 1. a. Brain structure comparisons of the following mice: Left: BTBR/R and B6 (normal mouse), Center: Comparison of BTBR/J and B6, Right: BTBR/J and BTBR/R. b. Diffusion tensor imaging to compare differences in nerve fibers. Red indicates the brain regions that were either bigger or had increased numbers of nerve fibers in BTBR/J mice in comparison to either B6 (left and center images) or BTBR/R (right image). Conversely, blue indicates brain regions in BTBR/J mice that were comparatively smaller or had decreased numbers of nerve fibers.These scans revealed particularly significant differences between BTBR/J and BTBR/R mice's corpus callosum. Credit: Molecular Psychiatry (2023). DOI: 10.1038/s41380-023-01999-z
Fig. 2. a–c. Comparison of the repeated sequence of copy number variations, including retrovirus genes on the genome. d and e. Gene expression level analysis of repeated sequences: BTBR mice had more copy numbers of the endogenous retrovirus gene ERV than normal (B6) mice, and a portion of these genes were activated in BTBR mice. Credit: Molecular Psychiatry (2023). DOI: 10.1038/s41380-023-01999-z
Fig. 3. a. AGM. B. Yolk sac: For BTBR/R autism model mice, genes with increased expression are indicated in pink and genes with decreased expression are in light blue. c–f. Comparison of gene expression levels in each cluster. In BTBR/R mice, there were changes in the expression of various genes (including stress response genes) that are indicative of endogenous retrovirus (ERV) activation. Credit: Molecular Psychiatry (2023). DOI: 10.1038/s41380-023-01999-z
Fig. 4. a: Open field experiment b. Light-dark box experiment c-e. ultrasonic vocalizations made by mouse pups when separated from the mother. f. ultrasonic vocalizations of adult mice (in the presence of a mouse of the opposite sex). g. Self-grooming behavior. h. Marble burying test. i. 3-chamber social interaction test. j. Barnes maze spatial learning test. BTBR/R and BTBR/J mice share key autistic-like behavioral abnormalities demonstrated in the results for experiments c through i. However, there are differences in anxious behavior (a, b) and spatial learning (j). BTBR/R mice did not demonstrate spatial learning difficulties. Therefore, BTBR/R is a more suitable model of autism than the existing BTBR/J model because it exhibited autistic-like behavior without compromised spatial learning ability. Credit: Molecular Psychiatry (2023). DOI: 10.1038/s41380-023-01999-z
Fig. 5. In BTBR autism model mice (BTBR/J and BTBR/R variants), retrovirus activation makes copy number variations occur easily. In other words, they could be said to evolve at a faster speed than normal mice. The supporting evidence for this is that although BTBR/J and BTBR/R mice share a common ancestry, a mere 30 years of being raised in different environments has led not only to behavioral differences between the two species but also significant differences in brain structure (i.e. BTBR/R mice have a functioning corpus callosum, while BTBR/J mice do not). Credit: Molecular Psychiatry (2023). DOI: 10.1038/s41380-023-01999-z