Autism spectrum disorder (ASD) affects over 1% of children in the United States, yet there remains relatively little understanding of underlying cause(s) and few options for therapeutic interventions. Our research team is evaluating an immune-based mechanism implicated in ASD ? prenatal exposure to maternal autoantibodies that target proteins in the developing fetal brain. A subset of mothers who have a child with ASD produce antibodies to fetal brain proteins that are critical for neurodevelopment, raising the possibility that these antibodies cross the placenta during gestation, interact with fetal brain protein targets, alter neurodevelopment, and lead to a maternal autoantibody related (MAR) form of ASD. We previously developed a passive transfer nonhuman primate model to determine if prenatal exposure to these autism-related autoantibodies alters offspring brain and behavioral development. Although this initial nonhuman primate model yielded promising results, the passive transfer approach relies on periodic injections of the autoantibodies into the pregnant dam and does not reflect a constant exposure throughout gestation, as is likely the case for a human fetus. We therefore initiated a new line of research to generate continuous autoantibody exposure rodent models that are reactive to the targeted epitope sequences specific to MAR risk for ASD, thus mimicking the human autoantibody profile. Rodent offspring continuously exposed to these antibodies during gestation demonstrate deficits in social development and repetitive behaviors paired with aberrant brain development. Our collaborative research team is now positioned to apply the techniques developed and tested in both the mouse and rat models to establish the first biologically relevant rhesus monkey model that will maintain a continuous exposure of autism-related autoantibodies prenatally. This will be accomplished through the following Specific Aims: (1) Develop the first nonhuman primate model to continuously produce anti-fetal brain antibodies throughout gestation and (2) Characterize the biodistribution of fetal brain-specific maternal autoantibodies in fetal rhesus monkeys at multiple time points during gestation. Establishing the nonhuman primate model will allow us to expand the period of in utero autoantibody exposure into the third trimester and provides an opportunity to evaluate the neurobiological effects in brain regions, such as prefrontal cortex, which are not well developed in rodents. At the conclusion of these studies, we will be well-positioned to utilize this sophisticated nonhuman primate model system to determine the mechanism by which prenatal exposure to maternal autoantibodies disrupts fetal brain development and explore, for the first time, therapeutic interventions to mitigate the effects of exposure.

Public Health Relevance

Autism spectrum disorder (ASD) affects over 1% of the children in the United States, yet there remains relatively little understanding of the underlying cause(s) and few options for therapeutic interventions. The proposed studies will evaluate a prenatal risk factor that has been implicated in ASD - maternal antibodies that can target the developing fetal brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH118574-01
Application #
9649533
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Winsky, Lois M
Project Start
2018-11-15
Project End
2020-10-31
Budget Start
2018-11-15
Budget End
2019-10-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Davis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618