In Vivo Magnetic Resonance Imaging and Spectroscopy Detect Alterations of Brain Metabolites in a Rat Model of Maternal Autoantibody-Related Autism
Dysregulation of the maternal immune system has been linked to various neurodevelopmental disorders in offspring, particularly Autism Spectrum Disorder (ASD). A number of recent studies, by our group and others, have focused on the relationship between the presence of specific autoantibodies found in the maternal circulation and the diagnosis of ASD in children. We previously characterized a set of antigenic epitopes on proteins, known to be important for neurodevelopment, which serve as targets for these maternally-derived autoantibodies and are present in up to 25% of mothers whose children go on to be diagnosed with ASD. Our work, and that of collaborators, has found ASD-relevant behavioral and cellular alterations in response to maternal autoantibody exposure during gestation in mouse, rat and non-human primate models. Specifically, embryonic studies suggest that the autoantibodies are able to bind radial glial cells in the developing cortex of rodents and influence progenitor cell migration, proliferation and subsequent neuronal cell size in adulthood.
We sought to examine the structural changes associated with the presence of maternal autoantibodies in our novel rat model of maternal autoantibody-related (MAR) ASD rat model. Further, as neurochemical imbalances are linked to ASD and these neurotransmitters and metabolic signals play an important role in brain development and function, we also aimed to evaluate the neurochemical profile in our rat model.
To develop our model, we first immunized rat dams with MAR-ASD specific peptides from LDHA, LDHB, CRMP1 and STIP1 to generate autoantibodies to these peptides in dams prior to breeding. Once offspring were born, we performed In vivo longitudinal magnetic resonance imaging and spectroscopy (MRI/S) in the frontal cortex of offspring to evaluate differences in levels of metabolites between MAR autoantibody exposed (n= 8) and control rats (n= 8) at pre- and post-pubertal time points (postnatal days 30 and 70, respectively).
Treatment of rat dams with MAR-ASD specific peptides resulted in high serum titers of antigen-specific peptides throughout and following gestation, as quantified by ELISA. Magnetic resonance spectroscopy analysis of frontal cortical neurometabolites in MAR-ASD exposed rat offspring evidenced altered levels of Taurine and Choline. Significant increases were seen in Taurine, alongside significant decreases in Choline levels at both 30 and 70-day time points. No specific differences were seen when evaluating sex as a variable.
As taurine is an abundant amino acid in the brain and choline-containing compounds are critical components of cell membranes and myelin, it is likely that altered levels of these metabolites in the frontal cortex may contribute, either directly or indirectly, to the ASD-relevant phenotypes seen in our MAR-ASD rat model.