Modeling exposure to folate receptor antibodies during neural development to understand its clinical significance.

Abstract

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder with defined core symptoms of impaired social communication, stereotyped or repetitive behaviors, and cognitive deficits. These core symptoms present early in childhood, which distinguishes this disorder from other neurological disorders that share similar characteristics. To our knowledge, there is currently no pharmacologic treatment for the core symptoms of ASD. A possible therapeutic strategy is supplementing folate, more specifically the reduced form, folinic acid, during pregnancy. Folate is the umbrella term for biological forms of vitamin B9. The well recognized role of folates as precursors of DNA synthesis, single carbon exchange reactions and in methylation reactions is a priori evidence of its requirement for cellular replication, metabolism, and epigenetic control of gene expression. This is especially important during the early stages of neural development. While the role of folate in cellular metabolism has been clearly defined, there has been no study, to our knowledge, that demonstrates the characteristics of folate uptake and distribution during gestation and early development. This is critical to understand because of the emerging findings that folate receptor alpha autoantibodies (FRAuAb) are linked to disruptions of neural development leading to ASD. Our lab has shown that a rat model of exposure to IgG antibodies specific to rat folate receptor alpha during gestation develops a behavioral phenotype comparable to the human ASD. This phenotype appears to be preventable with folinic acid and dexamethasone treatment. Preliminary observations in this model also suggest that the phenotype seen in rats directly exposed to FRAb is preserved in subsequent generations. Overall, this thesis provides new data on the uptake and distribution of folate and folate receptor antibodies in utero (Study 1, Part 1) and in juvenile stages of development (Study 1, Part 2) and observes an appearance of deficits to a subsequent generation of animals previously exposed to FRAb directly (Study 2)