Researchers at the UC Davis MIND Institute have created a mouse model for maternal antibody-related (MAR) autism spectrum disorder (ASD) that closely mimics the physiology and behaviors seen in people with this form of ASD. People with MAR ASD have been exposed to maternal autoantibodies, which can react with fetal brain tissue.
This model could help researchers investigate the neural damage associated with the condition. The study was published today in the journal Molecular Psychiatry.
“We’ve really needed an animal model that mimics what we see clinically,” said Judy Van de Water, professor in the UC Davis MIND Institute and Center for Children’s Environmental Health and senior author on the paper. “We can then understand the mechanisms, the pathology, and what the brains of these animals look like. In time, we might be able to use it to develop therapeutics.”
Van de Water goes into great detail about previous research on MAR ASD in a review that was published June 22 in Molecular Psychiatry.
While the adult blood-brain barrier is quite good at blocking antibodies, the fetal structure can be more porous and allow reactive maternal autoantibodies into the brain. This happens in about 25 percent of mothers whose children have ASD.
This research was inspired by the challenges faced by MAR ASD patients. The researchers wanted to create a model that incorporated these autoantibodies so they could investigate the molecular pathways involved. They also wanted to understand the roles maternal autoantibodies play in ASD. Are they actually causing damage or are they simply acting as proxy biomarkers for other mechanisms?
To create the model, the team identified the specific regions of the seven human proteins where antibodies bind. They then used these pieces of the total protein to generate similar autoreactivity in mice.
Once the model was created, they spent several months conducting behavioral and other tests to validate it. Specifically, the mice showed problems with social interaction and repetitive self-grooming. They also exhibited enlarged heads, similar to human MAR ASD behaviors and physical characteristics.
“We were able to replicate those behaviors across different tests and match these clinically to the kids who have this subtype of autism,” said postdoctoral researcher and first author Karen L. Jones. “Autism is a purely human disorder, you’re never going to have an autistic mouse. We were pleasantly surprised at how well the model maps to the human condition.”
Perhaps most importantly, the model showed that the maternal autoantibodies were actually causing the symptoms. “These antibodies absolutely have an effect on behavior,” said Van de Water.
This MAR ASD model may eventually help researchers investigate new treatments, but that won’t happen for some time. More immediately, the team wants to use it to study how these autoantibodies disrupt brain development.
“We want to understand how these antibodies are affecting the developing brain at the cellular level,” said Van de Water. “It’s a much more representative model than we’ve had in the past, which will help us conduct more detailed studies.”
Other authors include Michael C. Pride, Elizabeth Edmiston, Mu Yang, Jill L. Silverman and Jacqueline N. Crawley.
This research was supported by the NIEHS Center for Children’s Environmental Health (2P01ES011269-11), the Environmental Protection Agency (83543201), the NIEHS-funded CHARGE study (R01ES015359), and the NICHD-funded IDDRC 054 (U54HD079125), the Hearst Foundation, and The Hartwell Foundation.