New findings on autism development in mouse models

Autism is a common neurodevelopmental disorder, but the multiple factors behind its development are not yet fully understood. Often helpful in understanding the complex mechanisms behind BTBR/J, BTBR/J is the most commonly used mouse model in the world.

Currently, an international joint research project is being conducted by Professor Toru Takumi and Researcher Yoshifumi Hayashi of Kobe University. We have made new discoveries about the development of autism in mouse models.

In a series of detailed experiments and analyzes of BTBR/J mice and other subspecies BTBR/R, they revealed that endogenous retroviral activation increases fetal susceptibility to autism. They also found that BTBR/R exhibited autism-like behavior without impairing learning ability and was a more accurate model of autism than his widely used BTBR/J model. discovered.

Further research is expected to contribute to better classification of types of autism and the creation of new treatment strategies for neurodevelopmental disorders.

These research results molecule psychiatry March 7, 2023

main point

• The researchers analyzed BTBR/J, a widely used mouse model of autism, and its variant BTBR/R. using MRI. This revealed that the corpus callosum, which connects the left and right hemispheres of the brain, was compromised, but not in BTBR/J mice.
• Genomic and transcriptional analyzes showed that BTBR mice have increased levels of endogenous retroviral genes.
• In addition, single-cell RNA analysis in BTBR/R mice revealed altered expression of various genes, including stress response genes, indicative of endogenous retroviral activation.
• Although BTBR/J and BTBR/R mice share the same ancestor, various behavioral analysis experiments revealed differences in behavior such as spatial learning ability between the two model mice. rice field.

Research background

Autism (autism spectrum disorder) is a poorly understood neurodevelopmental disorder that is rapidly increasing in prevalence. Reasons for this continued increase in people diagnosed with autism include changing diagnostic criteria and the fact that older fathers are becoming more common. It is strongly associated with 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 elucidate the pathology of autism. Among these models, BTBR/J is a commonly used spontaneous mouse model of autism. Various abnormalities have been reported in BTBR/J mice, including damage to 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 strain exhibits autism-like behavioral abnormalities.

The aim of the current study was to shed light on the pathogenesis mechanisms of these autism-like behavioral abnormalities by performing a comparative analysis of BTBR/J and its subspecies BTBR/R.

research result

First, researchers performed MRI scans in BTBR/J and BTBR/R mice to investigate structural differences in each brain region. As a result, differences were found in 33 regions, including the amygdala, between BTBR/J and His BTBR/R mice. A particularly striking difference found was that the corpus callosum was impaired in BTBR/J, whereas BTBR/R was normal.

Next, the research group compared BTBR/R copy number variation with a normal mouse model using the array CGH method (B6). They found that BTBR/R mice had significantly increased levels of endogenous retrovirus (ERV) compared to B6 mice. Furthermore, qRT-PCR tests revealed that these retroviruses were activated in his BTBR/R mice. In B6 mice, on the other hand, there was no change in the expression of LINE ERVs, which fall within the same repeat sequence, indicating that this retroviral activation is specific to BTBR.

Subsequently, the researchers performed single-cell RNA analysis on tissues (AGM and yolk sac) from embryonic BTBR mice. The results provide evidence for her ERV activation in her BTBR mice, as expression changes were observed in a group of genes downstream of ERV.

Finally, researchers comprehensively explored differences between BTBR/J and BTBR/R at the behavioral level. The BTBR/R mouse was less anxious than the BTBR/J and exhibited qualitative changes in ultrasonic vocalizations measured as a way to assess the communicative competence of mice. BTBR/R mice also exhibited more self-grooming behavior and buried more marbles in the marble burial test. These two tests were designed to detect repetitive behavior abnormalities in people with autism. It was clear from the results that BTBR/R was more repetitive (i.e. more symptomatic) than her BTBR/J. Three-chamber social interaction testtmeasured how close mice approached one another, revealing more pronounced social impairments in BTBR/R than in BTBR/J mice (Figure 4i). Furthermore, a spatial learning test was performed using the Barnes maze, and the BTBR/J mouse had a reduced learning capacity compared to he B6 (normal mice). BTBR/R mice, on the other hand, showed similar abilities to B6.

Overall, this study reveals that retroviral activation increases copy number variants in BTBR mice, leading to behavioral and brain structural differences seen in BTBR/J and BTBR/R mice. (Figure 5).

further development

BTBR/J mice are widely used by researchers as a mouse model of autism. However, the results of this study highlight the usefulness of other strains of BTBR/R mice as they exhibit autism-like behavior without compromising spatial learning ability. The results also suggest that it may be possible to develop new treatments for autism that suppress ERV activation. In addition, subtypes of autism should be classified according to onset mechanisms. This is an important first step towards opening new avenues of treatment for autism.