Behavioral deficits in rats exposed folate receptor alpha antibodies in utero are transmitted to the next generation

Abstract Folate deficiency can lead to a myriad of disruptions in neurodevelopment including neural tube defects, developmental anomalies, and functional deficits, such as autism spectrum disorder (ASD). Folate receptor alpha (FRα) is the primary transporter of folate from the mother to the fetus and into the brain. A major subset of the ASD patients and their family members have autoantibodies against FRα that can block folate transport. Therefore, we investigated the effect of exposure to folate receptor alpha antibodies during fetal development, on behavioral deficits in the offspring in a rat model and determined if their deficits are passed on to a subsequent generation; thus, contributing to inheritance of the behavioral phenotype. We have produced a rat folate receptor alpha specific antibody (FRαAb) that when injected intraperitoneally into a dam on gestation day (GD)8, produces a litter with behavioral deficits in social communication, social interaction, including learning, memory, and cognition. Using this model, we tested the litter directly exposed to FRαAb and bred the offspring that had an affected phenotype to produce a litter that was not directly exposed to FRαAb. We observed social communication deficits and deficits in learning performance in both generations which provides preliminary evidence to indicate transmission of a behavioral phenotype associated with the FRαAb exposure to the next generation. This work supports the growing evidence that an altered maternal immune and/or micronutrient environment has a generational effect on ASD offspring, likely transmitted by non-Mendelian inheritance.