A model that mimics

“We’ve really needed an animal model that mimics what we see clinically,” says 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.”

The study was published June 28 in Molecular Psychiatry. Van de Water also goes into great detail about previous research on MAR ASD in a review that was published June 22 in the same journal.

“ASD is a very heterogenous disorder, with many unknown etiologies. MAR ASD is one such avenue to having a child with autism, and is based on the reactivity of maternal antibodies to proteins in the developing brain,” Van de Water notes. “We are just beginning to understand the different behavioral phenotypes associated with the presence of MAR autoantibodies. Once those studies are completed, we will have a better idea of how MAR ASD differs from other forms of idiopathic autism.”

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 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,” Van de Water points out. “The proof was based on the comparison between the animals that were exposed throughout gestation to the maternally derived autoantibodies and those animals whose dams were exposed to only saline. Studies are underway to determine what the cellular effects were, what the downstream pathway effects were and which of the antibodies are pathogenic and which, if any, are merely biomarkers for MAR autism.”

“Having a directed animal model allows us to better understand the ways in which the maternal antibodies alter the developing neurons,” she continued. “We know from earlier studies that the neurons are not destroyed by the antibodies, but rather have an altered developmental trajectory. Having a model that fully recapitulates what we see in humans will allow us to determine how these antibodies find their antigenic target, what happens when they bind to those targets and how this changes the downstream pathways of the developing brain.”

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.

“The development of a therapeutic based on the MAR ASD model is a long way in the future. We first need to understand how the antibodies act before we can determine a therapeutic course of action,” Van de Water tells DDNews. “This is definitely a future goal of the lab, however. We want to understand how these antibodies are affecting the developing brain at the cellular level. It’s a much more representative model than we’ve had in the past, which will help us conduct more detailed studies.”

“This publication was just the beginning of a series of follow-on studies to better understand the pathologic mechanisms associated with MAR ASD. Furthermore, we will soon publish a paper on the validation of maternal autoantibodies in the clinical population, and will create additional animals models to be understand each of the different autoantibodies and role that they play in a child developing autism,” she concludes.