Vitamin B9 (
folate)/B12 (
cobalamin) deficiency is known to induce brain structural and/or functional retardations. In many countries,
folate supplementation, targeting the most severe outcomes such as
neural tube defects, is discontinued after the first trimester. However, adverse effects may occur after birth because of some mild misregulations. Various hormonal receptors were shown to be deregulated in brain tissue under these conditions. The
glucocorticoid receptor (GR) is particularly sensitive to epigenetic regulation and post-translational modifications. In a mother-offspring rat model of
vitamin B9/B12 deficiency, we investigated whether a prolonged
folate supplementation could restore the GR signaling in the hypothalamus. Our data showed that a deficiency of
folate and
vitamin B12 during the in-utero and early postnatal periods was associated with reduced GR expression in the hypothalamus. We also described for the first time a novel post-translational modification of GR that impaired
ligand binding and GR activation, leading to decrease expression of one of the GR targets in the hypothalamus, AgRP. Moreover, this brain-impaired GR signaling pathway was associated with behavioral perturbations during offspring growth. Importantly, perinatal and postnatal supplementation with
folic acid helped restore GR
mRNA levels and activity in hypothalamus cells and improved behavioral deficits.