summary: Genomic and transcriptome analyzes revealed elevated levels of endogenous retroviral genes in the BTBR autism mouse model. His BTBR/R model of ASD showed differential expression of various genes indicative of endogenous retroviral activation. BTBR/R mice exhibit autism-like behavior without impairing learning ability.
sauce: Kobe University
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 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.
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 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 testing revealed that these retroviruses were activated in BTBR/R mice. In B6 mice, on the other hand, there was no change in the expression of LINE ERVs, which fall under the same repeat sequence, indicating that this retroviral activation is specific to her 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.
A three-chamber social interaction test, which measures how close a mouse approaches another mouse, also revealed a more pronounced social impairment in BTBR/R mice than in BTBR/J mice.
In addition, BTBR/J mice showed reduced learning ability compared to B6 (normal mice) when a spatial learning test was performed using the Barnes maze. 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. .
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.
Funding:
This research was supported by funding from organizations including:
See also
- Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (A).
- Japan Agency for Medical Research and Development “Brain Science Strategic Research Program (SRPBS)” (Psychiatric and Neurological Diseases)
- Takeda Science Foundation
About this genetics and autism research news
author: Verity Townsend
sauce: Kobe University
contact: Verity Townsend – Kobe University
image: Image credit to Neuroscience News.created by DALL-E2 Technology
Original research: open access.
“Old model with new insights: Endogenous retroviruses drive evolution to ASD susceptibility and hijack the transcriptional machinery during development]Toru Takumi and others molecular psychiatry
overview
Old model with new insights: Endogenous retroviruses drive evolution to ASD susceptibility and hijack the transcriptional machinery during development
BTBR T.+Itpr3tfThe /J (BTBR/J) strain is one of the most validated models of idiopathic autism and serves as a powerful forward genetics tool for analyzing the complexity of autism.
A sister strain, BTBR TF/ArtRbrc (BTBR/R), with an intact corpus callosum, showed more prominent core symptoms of autism but moderate ultrasound communication/normal hippocampus-dependent memory. , which may mimic autism on the high-functioning spectrum.
Interestingly, perturbation of epigenetic silencing mechanisms increases the formation of de novo copy number variations (CNVs) in two BTBR strains of hyperactive endogenous, a migratory genetic component of ancient retroviral infection. It leads to sexual retrovirus (ERV).
This feature makes the BTBR strain a multi-locus model that is still evolving towards greater ASD susceptibility.
Moreover, active ERVs, similar to viral infections, evade the integrated stress response (ISR) of host defenses and hijack the transcriptional machinery during embryonic development in the BTBR strain.
These results suggest a dual role for ERV in ASD pathogenesis, driving host genome evolution on a long-term scale, directing cellular pathways in response to viral infection, and immediately affecting embryonic development. give
Expression of wild-type draxin in BTBR/R also provides a more accurate model for investigating the central pathogenesis of autism without the interference of impaired forebrain bundles as in BTBR/J .
