Autism susceptibility in a mouse model associated with endogenous retroviruses

The complex mechanisms underlying the development of autism (autism spectrum disorder; ASD) are not fully understood, and researchers studying neurodevelopmental disorders generally focus on animals, particularly mice. I am using model. A strain of mice known as BTBR/J is the most commonly used mouse model of idiopathic autism. An international collaboration led by Dr. Toru Takumi of Kobe University and his researcher, Dr. Chia-wen Lin, has made new findings that help explain the development of autism in mouse models.

Combined detailed imaging and behavioral experiments using the BTBR/J mouse model and its sister mouse strain, BTBR/R, show that endogenous retroviral (ERV) activation sensitizes fetuses to autism suggests that The researchers also found that BTBR/R mice exhibited autism-like behavior without impairing learning ability. This suggests that this strain is a more accurate model of autism than the widely used His BTBR/J model.

It is hoped that further research will contribute to a better classification of autism types and indicate new therapeutic strategies for neurodevelopmental disorders. molecular psychiatry (“Old model with new insights: Endogenous retroviruses drive evolution to ASD susceptibility and hijack the transcriptional machinery during development), the scientists said their study “explains the idiopathic pathogenesis of the BTBR strain by implicating it as a superimposed model of multiple genetic mechanisms and viral infections.” , suggested that targeting enhanced ERV activity or its infectious process in BTBR mice would be the next step towards developing possible therapeutic strategies for the immunodysregulated subtype of ASD.

“ASD is a neurodevelopmental disorder with a complex genetic makeup and heterogeneity, with a prevalence of 2.3% in 2018, which has hampered the development of therapeutic strategies for this disease,” the team said. increase. Reasons for this continued increase in people being diagnosed with autism include changing diagnostic criteria and aging fathers becoming more common.

Autism is strongly associated with genetic factors and can be caused by abnormalities in DNA structure such as copy number variations (CNVs). “…accumulating evidence suggests a prominent role for CNVs, large-scale structural chromosomal variations, directly contributing to ASD pathology or ASD susceptibility,” the researchers added. .

Animal models, especially mice, are often used in research to elucidate the pathology of autism. Among these models, BTBR/J is a commonly used mouse model of spontaneous 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 newly reported study was to shed light on the underlying mechanisms of behavioral disorders such as autism. I did a comparative analysis.

The researchers first performed MRI scans in BTBR/J and BTBR/R mice to investigate structural differences in brain regions. As a result, he revealed differences between BTBR/J and BTBR/R mice in 33 regions, including the amygdala. A particularly striking difference is that the corpus callosum is impaired in BTBR/J animals, whereas this part of the brain is normal in BTBR/R animals. The corpus callosum is the region of the brain that connects the left and right hemispheres.

The research group then used array-based comparative genomic hybridization to compare CNVs in BTBR/R and normal B6 mouse models. Results revealed that BTBR/R animals had significantly increased levels of endogenous retroviruses (ERVs) compared to B6 mice. “ERVs are relics of ancient retroviral infections in the germ line.”Interestingly, by analyzing the repeat sequences of the identified CNVs, we found that ERVs were involved in speeding up CNV formation in both BTBR strains. We found that it could be,” they said.

Subsequent qRT-PCR analysis showed that these retroviruses were activated in BTBR/R mice, and comparative studies in B6 animals indicate that this retroviral activation is specific to BTBR. increase. Single-cell RNA analysis of BTBR/R mice revealed altered expression of various genes, including stress response genes, indicative of endogenous retroviral activation.

Single-cell RNA analysis of BTBR mouse embryo tissues provided further evidence of ERV activation in these animals, as expression changes were observed in a group of genes downstream of ERV. “…single-cell RNA sequencing (scRNA seq) identified evidence of her ERV activation during embryonic development,” they further state.

Also, although BTBR/J and BTBR/R mice share the same ancestry, experiments revealed differences in spatial learning abilities and other behaviors between the two model mice. The researchers conducted a series of experiments to comprehensively explore differences between BTBR/J and BTBR/R at the behavioral level. “A behavioral test battery was performed to compare BTBR/R and BTBR/J, using B6 as a control,” they said.

The results of these tests showed that BTBR/R mice were less anxious than BTBR/J animals 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. “BTBR/R spent about 30% more time self-grooming than BTBR/J mice. , showed an even stronger repetitive behavior phenotype.” These two tests were designed to detect repetitive behavior abnormalities in autistic individuals. The results revealed that the BTBR/R mice exhibited more repetitive behaviors (more symptomatic) than her BTBR/J mice.

A three-chamber social interaction test, which measures how close a mouse approaches another mouse, also revealed more pronounced social deficits in BTBR/R than in BTBR/J mice. In addition, as a result of spatial learning experiments using the Barnes maze, BTBR/J mice showed lower learning ability than B6 (normal mice), whereas BTBR/R mice showed learning ability equivalent to that of normal B6 animals. I was. “…Barnes maze analysis of hippocampal-dependent memory showed that BTBR/R tended to learn the task faster than B6 and had similar latencies to goal at the end of training, whereas BTBR/J Performance was declining throughout the training period.”

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. . “Interestingly, perturbation of epigenetic silencing mechanisms leads to hyperactive ERVs, the migratory genetic component of ancient retroviral infections, that increase de novo CNV formation in two BTBR strains.” they said. “This feature makes the BTBR strain a multi-locus model that continues to evolve towards greater ASD susceptibility. and have a lasting effect on embryonic development.”

BTBR/J mice are widely used by researchers as a mouse model of autism. Newly reported findings highlight the utility of other strains of BTBR/R mice to exhibit autism-like behavior without compromising spatial learning ability. “With new advances on this old model, our study provides insight into how ASD susceptibility evolves in the genome, and BTBR as a precise model for investigating the central pathogenesis of autism.” /R,” the team pointed out.The results also suggest that it may be possible to develop new treatments for autism that suppress ERV activation. However, there is a need to classify subtypes of autism according to onset mechanisms. This is an important first step towards opening new avenues of treatment for autism.