The imbalance of prenatal micronutrients may perturb one-carbon (C1) metabolism and increase the risk for neuropsychiatric disorders. Prenatal excessive methionine (MET) produces in mice behavioral phenotypes reminiscent of human schizophrenia. Whether in-utero programming or early life caregiving mediate these effects is, however, unknown. Here, we show that the behavioral deficits of MET are independent of the early life mother-infant interaction. We also show that MET produces in early life profound changes in the brain C1 pathway components as well as glutamate transmission, mitochondrial function, and lipid metabolism. Bioinformatics analysis integrating metabolomics and transcriptomic data reveal dysregulations of glutamate transmission and lipid metabolism, and identify perturbed pathways of methylation and redox reactions. Our transcriptomics Linkage analysis of MET mice and schizophrenia subjects reveals master genes involved in inflammation and myelination. Finally, we identify potential metabolites as early biomarkers for neurodevelopmental defects and suggest therapeutic targets for schizophrenia.
The necessity for a finely tuned one-carbon (C1) metabolism activity during pregnancy is supported by the role of micronutrients such as methionine, choline, vitamin B12, betaine, and folate in brain development through involvement in methylation processes1,2,3,4,5,6,7,8,9. C1 metabolism encompasses two complex pathways, the transmethylation (methionine) and the folate cycles, through which a carbon unit is transferred from one to the other metabolic pathways. Dietary or supplementary methionine is converted to S -adenosyl-methionine (SAM), the main methyl donor that is used in almost all methylation reactions, where it is converted to S -adenosyl-homocysteine (SAH) (Fig. 2d). SAH is converted to homocysteine (Hcy), a potent neurotoxin, which can then be recycled to methionine by receiving methyl group provided by the folate cycle. Methylation mediated through the C1 pathways is a universal reaction that plays a critical role in numerous biological processes and metabolic pathways that are involved in cell proliferation, differentiation, survival, and other cellular functions10,11,12,13,14.
Fluctuations in the methyl-donor dietary intake during pregnancy have been shown to cause changes in the components of the C1 pathways and in the levels of DNA methylation15.