Studying Microglia as Possible Therapeutic Targets for Autism Spectrum Disorder (ASD) in a Mouse Model of Maternal Anti-Caspr2 Antibody-Induced ASD
Abstract
Autism spectrum disorder (ASD) incidence continues to rise worldwide with boys being 4 times more likely to be affected than girls. At the same time, ASD treatments are limited to symptom management. This proposal addresses several Fiscal Year 2021 (FY21) ARP Areas of Interest, including assessing new therapeutics and addressing environmental risk factors. Since ASD originates from insults to the developing brain, the in utero environment with exposure to toxins, viruses, and brain reactive antibodies has been linked to increased risk for ASD. Our studies have been focused on the maternal antibodies, antibodies that are transferred from the mother to the fetus and can affect the developing brain. During pregnancy, antibodies from the mother cross the placenta and are transferred to the fetus. This provides the developing fetus a defense mechanism against pathogens. However, the antibodies can reach every organ of the fetus, including the brain, because at this time the barrier between the blood and the brain is not fully matured. Therefore, maternal antibodies that target antigens in the fetal brain may affect development during a critical time window. We and others have found that one in every 10-20 mothers with an ASD child harbors antibodies against brain antigens. Exposure in utero to maternal antibodies can therefore explain a significantly larger proportion of ASD than new or rare inherited mutations, which are considered major ASD risk factors. Our studies have been focused specifically on an antibody that binds Caspr2 protein. This protein is known to be important in the developing brain and mutations in Caspr2 have been associated with neurodevelopmental disorders in humans. Importantly, these antibodies are present at high frequency in mothers with brain-reactive antibodies and an ASD child. We found that male mice, but not female mice, exposed in utero to anti-Caspr2 antibody show structural abnormalities in the developing brain. As adults, they display ASD-like behavioral abnormalities. Interestingly, neurons of mice exposed in utero to anti-Caspr2 antibody have fewer branches, meaning they are forming fewer connections with other brain cells compared to mice exposed to an antibody that does not bind brain. Microglia are brain immune cells that are responsible to maintain the integrity of neurons. We found that mice exposed in utero to anti-Caspr2 antibody have hyper-activated microglia, and that depletion of microglia mitigates the ASD–like phenotype at the time of depletion but not when microglia are reconstituted in the brain. Interestingly, we also found by studying the gene expression level of microglial cells from adult mice exposed in utero to anti-Caspr2 antibody that the microglia cells show an immature gene profile, arresting them in a an hyper-activated state, compared to microglia from mice exposed in utero to Control antibody. Given that activated microglial cells have sex-dependent long-term effects on the developing brain, we hypothesize that exposure in utero to anti-Caspr2 antibody affects microglial programming in male, but not female, mice and thus arrests the microglia in an immature stage, resulting in ASD-like phenotype. Therefore, it is our hypothesis that suppressing microglial activation will reverse the ASD-like phenotype. In Aim 1, we use a drug that is FDA-approved (captopril) and has been shown to be safe to suppress microglia activation rather than depleting them because it has more relevance to the clinic, and long-term depletion can affect the wiring of the brain and behavior. In this aim, we will test whether we can reverse or mitigate the ASD-like phenotype in mice exposed in utero to anti-Caspr2 antibody. In a pilot study, we were able to show that we can suppress microglia activation in male mice exposed in utero to anti-Caspr2 IgG treated with captopril. In Aim 2, since in utero environmental signals can affect specific stage of microglia devel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210880
Entities
People
- Lior Brimberg
Organizations
- The Feinstein Institute for Medical Research
- United States Army