Resume: Genome and transcriptome analysis revealed that BTBR autistic mouse models have increased levels of endogenous retrovirus genes. BTBR/R models of ASD showed differences in the expression of several genes indicative of endogenous retrovirus activation. BTBR/R mice display autistic behavior without impaired learning.
Source: University of Kobe
Autism (autism spectrum disorder) is a neurodevelopmental disorder that remains largely unexplored despite the rapidly increasing number of patients.
Reasons for this continued increase in people diagnosed with autism include changes in diagnostic criteria and the increased incidence of older fathers.
Autism is strongly related to genetic factors and can be caused by abnormalities in DNA structure, such as variations in copy number.
Animal models, especially mice, are often used in research to elucidate 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 several abnormalities in BTBR/J mice, including deterioration of the corpus callosum (which connects the left and right hemispheres of the brain) and excessive immune system signaling.
However, it is not entirely clear why this particular lineage exhibits autistic-like behavioral abnormalities.
The aim of the present study was to shed light on the mechanism of origin of these autistic-like behavioral abnormalities by performing a comparative analysis on BTBR/J and its subspecies BTBR/R.
Research results
First, the researchers performed MRI scans on BTBR/J and BTBR/R mice to examine structural differences in each brain region.
The results showed that there were differences between BTBR/J and BTBR/R mice in 33 regions, including the amygdala. A particularly striking difference discovered was that while the corpus callosum of BTBR/J is damaged, that of BTBR/R is normal.
The research group then used the array CGH method to compare the copy number variations of BTBR/R with those of a normal mouse model (B6). They revealed that BTBR/R mice had significantly elevated levels of endogenous retroviruses (ERV) compared to B6 mice.
In addition, qRT-PCR testing revealed that these retroviruses were activated in BTBR/R mice. On the other hand, in B6 mice, there was no change in the expression of LINE ERV (which is classified in the same repetitive sequence), indicating that this retroviral activation is specific for BTBR.
Next, the researchers performed single-cell RNA analysis on the tissue of embryonic BTBR mice (on the AGM and yolk sac). The results provide evidence of ERV activation in BTBR mice, as expression changes were observed in a group of genes downstream of ERV.
Finally, the researchers have done extensive research into the differences between BTBR/J and BTBR/R at the behavioral level. BTBR/R mice were less anxious than BTBR/J and showed qualitative changes in ultrasonic vocalizations, which are measured as a means of assessing mice’s communicative ability.
BTBR/R mice also showed more self-grooming behavior and buried more marbles in the marble burial test.
These two tests are designed to detect repetitive behavioral abnormalities in autistic individuals. The results clearly showed that BTBR/R is more repetitive (ie more symptomatic) than BTBR/J.
The 3-chamber social interaction test, which measures how close a mouse approaches another mouse, also showed more pronounced social deficits in BTBR/R than in BTBR/J mice.
In addition, a Barnes maze was used to perform a spatial learning test, where BTBR/J mice showed impaired learning compared to B6 (normal mice). In contrast, BTBR/R mice showed similar potency to B6.
Overall, the study revealed that retrovirus activation causes copy variant numbers to increase in BTBR mice, leading to the differences in behavior and brain structure seen in BTBR/J and BTBR/R mice.
Further developments
BTBR/J mice are widely used by researchers as a mouse model for autism. However, the results of this study highlight the utility of the other lineage of BTBR/R mice, as they exhibit autistic behavior without compromising spatial learning. The results also suggest that it may be possible to develop new treatments for autism that suppress ERV activation.
In addition, it is necessary to classify autism subtypes according to their mechanism of origin, which is an essential first step towards opening up new treatment options for autism.
financing:
The study was supported by funding from the following organizations, among others:
Also see
- Grants-in-Aid for scientific research (A) from the Japan Society for the Promotion of Science.
- The “Strategic Research Program for Brain Sciences (SRPBS)” of the Japan Agency for Medical Research and Development (Psychiatric and Neurological Disorders)
- Takeda Science Foundation
About this genetics and autism research news
Author: Really Townsend
Source: University of Kobe
Contact: Verity Townsend – University of Kobe
Image: The image is credited to Neuroscience News. Made with DALL-E 2 technology
Original research: Open access.
“An old model with new insights: endogenous retroviruses drive development towards ASD susceptibility and hijack transcriptional machinery during development” by Toru Takumi et al. Molecular Psychiatry
Abstract
An old model with new insights: endogenous retroviruses drive evolution towards ASD susceptibility and hijack transcriptional machinery during development
The BTBR T+Itpr3tf/J (BTBR/J) strain is one of the most valid models of idiopathic autism and serves as a powerful genetic tool to dissect the complexity of autism.
We found that a sister strain with an intact corpus callosum, BTBR TF/ArtRbrc (BTBR/R), showed more prominent core symptoms of autism, but moderate ultrasound communication/normal hippocampus-dependent memory, which may mimic autism on the high-functioning spectrum.
Intriguingly, a disrupted epigenetic silencing mechanism leads to hyperactive endogenous retrovirus (ERV), a mobile genetic element of ancient retroviral infection, that increases de novo copy number variation (CNV) formation in the two BTBR strains.
This feature makes the BTBR strain a still-evolving multi-loci model toward higher ASD sensitivity.
Moreover, analogous to virus infection, active ERV evades the integrated stress response (ISR) of the host defense system and hijacks the transcriptional machinery during embryonic development in the BTBR strains.
These results suggest a dual role of ERV in the pathogenesis of ASD, driving long-term host genome evolution and managing cellular pathways in response to viral infection, which has immediate effects on embryonic development.
The wild-type Draxin expression in BTBR/R also makes this substrain a more accurate model to investigate the core etiology of autism without the interference of damaged forebrain bundles as in BTBR/J.